Abstract
Inflammatory bowel disease (IBD) is an idiopathic chronic inflammatory disease of the gastrointestinal system. The spectrum is of predominantly two types, namely, ulcerative colitis and Crohn’s disease. The incidence of IBD has been increasing steadily since 1990, and so the number of agents used in their treatment. Biologics that are derived partly or completely from living biological sources such as animals and humans have become widely available, which provide therapeutic benefits to the IBD patients. Currently, monoclonal antibodies against tumor necrosis factor-alpha (infliximab, adalimumab, certolizumab, and golimumab), integrins (vedolizumab and natalizumab), and interleukin (IL)-12 and IL-23 antagonists (ustekinumab) are approved for use in IBD. Biosimilars of infliximab and adalimumab are also available for the treatment of IBD. This review summarizes the clinical pharmacology, studies leading to their approval, overall indications and their use in IBD, usage in pregnancy and lactation, and the adverse effects of these agents. This review also summarizes the recent advances and future perspectives specific to biologics and biosimilars in IBD.
Introduction
The inflammatory bowel disease (IBD) comprises two types, namely, the ulcerative colitis (UC) and Crohn’s disease (CD). They are a spectrum of chronic idiopathic autoimmune inflammatory disorders with remission and relapses, primarily affecting the gastrointestinal system.Citation1 It was traditionally regarded as the disease of the westernized nations, but in the 21st century, the epidemiology of IBD is fast changing.Citation2 A systematic review reports that the highest prevalence of IBD is seen in Europe (UC 505 per 1,00,000 in Norway and CD 322 per 1,00,000 in Germany) and North America (UC 286 per 1,00,000 in the USA and CD 319 per 1,00,000 in Canada).Citation3 It also reports that the incidence has been rising since 1990 in newly industrialized countries of Africa, Asia, and South America. For example, the annual percentage change of UC and CD in Brazil was +14.9% (95% CI 10.4, 19.6) and +11.1% (95% CI 4.8, 17.8), respectively, whereas in Taiwan, it was +4.0% (95% CI 1.0, 7.1) and +4.8% (95% CI 1.8, 8.0), respectively.Citation3 UC is characterized by confluent mucosal inflammation and erosions starting from the anal verge and extending to a variable extent.Citation4 CD is a transmural inflammation of any part of the gastrointestinal tract with characteristic rectal sparing and skip lesions often associated with extraintestinal manifestations involving the joint, skin, or eyes.Citation5 Patients often complain of diarrhea associated with rectal bleeding, abdominal tenderness, and weight loss.Citation6,Citation7
Etiopathogenesis of IBD comprises genetic components, environmental factors, microbial flora of the gut, and immune responses.Citation8 However, the main mechanism seems to be the bacterial antigens gaining access to the antigen-presenting cells through the impaired epithelial barrier. There are interleukin (IL)-12- and IL-18-mediated type 1 helper T-cell responses in CD and IL-4-mediated type 2 helper T-cell responses in UC.Citation9 The balance between pro-and anti-inflammatory responses is governed by regulatory TH17 and Treq cells as both of them serve to limit immune and inflammatory responses in the gut.Citation9 The T cells further govern the release of IFN and tumor necrosis factor (TNF) that recruit macrophages, which in turn positively regulate T helper cells.Citation9 Finally, the recruited inflammatory cells gain access to the site of inflammation with the help of cell adhesion molecules such as integrins.Citation9
Medical therapy of IBD is complex as the disease etiology is multifactorial and the primary aim of pharmacotherapy is to dampen the generalized inflammatory response, thereby relieving symptoms.Citation10 Off late importance has been given to mucosal healing as well.Citation10 The specific goals of treatment in IBD include the control of acute exacerbation, maintenance of relapses, treatment of specific complications, and surveillance of malignant transformation.Citation11 Traditionally, the drugs used in the treatment of IBD are mesalamine derivatives (mesalamine, sulfasalazine, olsalazine, and balsalazide), glucocorticoids (prednisolone, methylprednisolone, hydrocortisone, and budesonide), and immunomodulators (6-mercaptopurine, azathioprine, methotrexate, cyclosporine, and tacrolimus).Citation10 With the advent of advances in medical science and technology, a new group of drugs emerged for various chronic disease conditions called the biologics that are derived partly or completely from living biological sources such as animals and humans.Citation12 The most widely used biologics are the TNF-α inhibitors such as adalimumab, certolizumab, golimumab, and infliximab, which are highly effective in the treatment of both UC and CD. The other biologic agents in IBD include the integrin receptor antagonists, namely, vedolizumab and natalizumab, and IL-12 and IL-23 antagonist, ustekinumab.Citation13 This review summarizes the clinical pharmacology, overall indications and their use in IBD, usage in pregnancy and lactation, and the adverse effects of these agents and their biosimilars.
We have summarized various approved agents for current use in IBD and their recommended dosage regimen in . Some of the biologics in the Phases II and III of their development along with their mechanism of action as registered in the global clinical trial registry (www.clinicaltrials. gov) for use in IBD are summarized in . Similarly, the biosimilars in the pipeline at various stages of development for use in IBD and their status in various countries of the world are summarized in .
Review methodology
Studies were searched in electronic databases according to article titles, abstract contents, and relevance in the field of biologics and biosimilars in IBD. The database used in this review included PubMed, MEDLINE, Embase, Google Scholar, Scopus, ClinicalTrials.gov, US Food and Drug Administration (FDA), European Medicines Agency, and Cochrane databases. We also manually searched references to identify additional relevant studies. The “Keywords” above were used to locate relevant journal articles. Here, we provide a comprehensive narrative literature review of the role of biologics and biosimilars in IBD as well as discuss and highlight the clinical pharmacology, overall indications and their use in IBD, usage in pregnancy and lactation, and the adverse effects of these agents and their biosimilars.
Discussion
TNF-α inhibitors
Adalimumab (Humira®)
Mechanism of action and indications
Adalimumab is the first fully human monoclonal antibody (MAb) that was approved by the FDA in 2002 for rheumatoid arthritis (RA).Citation14 It was initially named as D2E7 marketed by Abbott Laboratories (Chicago, IL, USA) and currently owned by AbbVie (Chicago, IL, USA).Citation15 The name Humira stands for human MAb in RA. It is a recombinant human immunoglobulin (Ig)-G1 MAb created using the phage display technology.Citation16 It inhibits TNF-α, which is a cytokine involved in normal inflammatory and immunological responses, and it inhibits its interaction with p55 and p75 cell surface TNF-alpha receptors. It does not have action on TNF-beta.Citation16 It also causes changes in the levels of adhesion molecules that are responsible for leukocyte migration. Adalimumab is indicated for use in moderate-to-severe RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, moderate-to-severe CD and UC with inadequate response to conventional therapy, moderate-to-severe chronic plaque psoriasis, hidradenitis suppurativa, uveitis, and Behcet’s disease.Citation17 It is available as a sterile, preservative-free solution in the pen of 80 and 40 mg, the prefilled syringes of 80, 40, 20, and 10 mg, and a single use institutional vial of 40 mg, which are to be given subcutaneously (SC).Citation14 The bioavailability of the agent is 64% with a half-life of ~2 weeks following linear kinetics of elimination.Citation14
Dosing in CD
The recommended dose regimen for use in CD in adults is 160 mg on day 1, 80 mg on day 15, and a maintenance dose of 40 mg every alternate week starting at day 29 for not >1 year.Citation14 The evidence for the use of adalimumab in CD stems from three main clinical trials, namely, CLASSIC (clinical assessment of adalimumab safety and efficacy studied as induction therapy in CD), CHARM (Crohn’s trial of the fully human antibody adalimumab for remission maintenance), and GAIN (gauging adalimumab efficacy in infliximab nonresponders).Citation18 The CLASSIC-I trial is a dose-ranging randomized controlled trial (RCT) with 299 moderate-to-severe CD patients naive to TNF-α inhibitor therapy who were randomized to receive adalimumab (40/20, 80/40, or 160/80 mg) or placebo at weeks 0 and 2. The remission rates (primary endpoint) defined as CD activity index (CDAI) <150 at week 4 were 18% (P=0.36), 24% (P=0.06), and 36% (P=0.001), respectively, and 12% in the placebo group.Citation19 A total of 275 patients from CLASSIC-I entered the CLASSIC-II RCT where all patients received 40 mg adalimumab at weeks 4 and 6 of CLASSIC-I. A total of 55 patients who were at remission during both the dosing of CLASSIC-II were re-randomized into adalimumab 40 mg every other week (EOW), weekly, or placebo through 56 weeks. The rates of remission were 79%, 83%, and 44%, respectively. The remaining 204 patients who were not on remission while entering CLASSIC-II were subjected to adalimumab 40 mg EOW open label with the option to increase the dose to 40 mg weekly in case of a nonresponse or flare, and at 56 weeks, 46% were at remission.Citation20 In CHARM trial, ~40% of the 499 patients with moderate-to-severe CD had clinical remission at 26 and 52 weeks suggesting long-term efficacy.Citation21 In case of the GAIN trial conducted among patients who had either lost response or were intolerant to infliximab, patients were randomized to receive either adalimumab induction therapy or placebo and 21% achieved remission while approximately half demonstrated clinical benefit.Citation22 A study done by Cote-Daigneault et al has shown the evidence for efficacy in fistulizing CD and in achieving mucosal healing in CD unlike certolizumab and in UC.Citation23 Adalimumab is indicated in pediatric CD. IMAgINE 1 and IMAgINE 2 are the two trials showing the evidence of efficacy and safety of adalimumab in pediatric population. The IMAgINE 1 trial was conducted in 192 children with CD not responding to conventional therapy. After an open-label induction therapy with SC adalimumab at weeks 0 and 2, 188 children at week 4 were randomized to receive double-blind maintenance therapy with either high dose (40 or 20 mg for body weight ≥40 or <40 kg; n=93) or low dose (20 or 10 mg for body weight ≥40 or <40 kg; n=95) of adalimumab alternate week for 48 weeks. At week 26, 63 (33.5%) of the 152 patients who completed 26 weeks were in clinical remission. High- and low-dose groups (36/93 [38.7%] versus 27/95 [28.4%]) showed no significant difference (P=0.075).Citation24 Patients who completed IMAgINE 1 were eligible to enroll in IMAgINE 2. A total of 100 children participated for up to 240 weeks. A total of 41% and 48% achieved remission (pediatric CDAI ≤10) and response (pediatric CDAI decrease ≥15 from IMAgINE 1 baseline) at 240 weeks, respectively. The safety profile was similar to those in adult CD trials with adalimumab and IMAgINE 1 trial.Citation25
Dosing in UC
The recommended dose regimen for UC is 160 mg SC on day 1 (or 80 mg on two consecutive days) followed by a dose of 80 mg on day 15 and, 2 weeks later (day 29), continues with a dose of 40 mg EOW.Citation14 A meta-analysis of three RCTs reported that adalimumab 160/80 mg was more efficacious when compared with placebo for the induction of clinical remission (relative risk [RR] 1.62, 95% CI 1.15, 2.29) and clinical response (RR 1.37, 95% CI 1.19, 1.59). Similarly, adalimumab 40 mg EOW was more effective than placebo in maintaining clinical remission (RR 2.38, 95% CI 1.57, 3.59) and clinical response (RR 1.69, 95% CI 1.29, 2.21).Citation26
Side effects
The most serious adverse reactions encountered in clinical trials were serious infections due to immunosuppression, malignancies, and demyelinating neurological disease.Citation14 Serious infections include pneumonia, septic arthritis, prosthetic/postsurgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis at an incidence rate of 0.04/patient-year (PY) when compared with 0.02/PY in the placebo arm.Citation14 The most frequently encountered malignancies other than lymphoma and nonmelanoma skin cancers (NMSC) include breast cancer, colon cancer, lung cancer, melanoma, and prostate cancer at a rate of 0.6 (95% CI 0.3, 1.0)/100 PYs in 3853 adalimumab (Humira)-treated patients for a median duration of 5.5 months versus 0.4 (95% CI 0.2, 1.0)/100 PYs in 2183 controls for a medical duration of 3.9 months. However, based on a recent pooled estimate from 23,458 patients treated with adalimumab on comparison with age- and sex-matched populations, the observed number of malignancies in each disease population was reported to be similar to the expected number in the reference population.Citation27 The rates for lymphomas (0.1/100 PYs) and NMSC (0.2/100 PYs) were very low.Citation27 Some of the common side effects include injection site pain and reaction, hypersensitivity, and gastrointestinal disturbances. In contrast, rare adverse effects result in the reactivation of latent tuberculosis, autoantibody production leading to a lupus-like syndrome, blood dyscrasias, congestive cardiac failure, and interstitial lung diseases.Citation28 Humira comes under category B for its use in pregnancy as animal studies have proven to be safe but controlled studies in humans are lacking.Citation14 Its use in lactation is based on the benefit–risk ratio as decided by the doctor because it is unknown if adalimumab is excreted in breast milk or absorbed systemically.Citation14 Its use in children has not been evaluated, and it should be used judiciously in geriatric population as there is already an increased risk of infections and malignancies in elderly.Citation14
Certolizumab pegol (Cimzia®)
Mechanism of action and indications
Certolizumab pegol is a monoclonal antibody (MAb) manufactured by Union Chimique Belge (UCB) Pharmaceuticals (Brussels, Belgium) and subsequently approved by the FDA in April 2008 for CD.Citation29 Certolizumab pegol is a recombinant antigen-binding fragment (Fab) antibody against TNF-α, which is conjugated to 40 kDa polyethylene glycol, thereby enhancing the bioavailability, drug stability, and plasma half-life.Citation30 The molecular mass of the Fab antibody fragment alone is 47.8 kDa. It is the only crystallizable fragment (Fc)-free PEGylated TNF-α inhibitor, so it does not fix complement or cause antibody-dependent cell-mediated cytotoxicity.Citation30 The FDA-approved indications are moderate-to-severely active CD or RA, active psoriatic arthropathy, and ankylosing spondylitis.Citation29 It is available as powdered reconstitution form, which contains 200 mg of sterile, white, lyophilized powder, and as prefilled syringe, which is a single-use, 1 mL prefilled glass syringe with a fixed 25 G 1/2 in thin wall needle, providing a dose of 200 mg/1 mL.Citation29 Upon single SC dose or intravenous (IV) dose, there was a predictable dose-related plasma concentration. There is a linear relationship between the dose given and the maximum plasma concentration (Cmax) and the area under the curve over time. Though metabolism studies have not been performed in humans, animal studies suggest that polyethylene glycol polymers are excreted unchanged in urine and the terminal plasma half-life is ~14 days.Citation29
Dosing in CD
The recommended regimen in CD is the SC administration of 400 mg initially and at weeks 2 and 4. If there is response, 400 mg SC is given once in every 4 weeks for maintenance.Citation29 The efficacy of certolizumab is proven by the PRECiSE-1 study, which was an RCT done at 171 sites where 331 patients with moderate-to-severe CD were randomized to receive 400 mg certolizumab and 328 patients received placebo. At week 6, clinical response (100-point reduction in CDAI score) was 35% when compared with 27% in the placebo group (P=0.02). At week 26, the clinical remission (CDAI ≤150 points) was 29% in the certolizumab group versus 18% in the placebo group (P<0.05).Citation31 Fistula closure rates were same at short term and long term with certolizumab when compared with placebo.Citation31 PRECiSE-2 study evaluated patients who had clinical response with certolizumab at week 6 and were randomized to receive certolizumab 400 mg (n=216) or placebo (n=212) every 4 weeks over weeks 8–24 for maintenance therapy. The remission rates were 48% and 29%, respectively, at week 26.Citation32 Patients completing PRECiSE-1 and -2 received open-label certolizumab 400 mg every 4 weeks for 7 years in PRECiSE-3 trial, and the clinical remission rate was ≥68% at each year based on observed cases.Citation33 Patients who relapsed in PRECiSE-1 and PRECiSE-2 received certolizumab re-induction followed by 400 mg every 4 weeks maintenance for 360 weeks and the overall remission rates at weeks 52, 156, and 362 were 64%, 64%, and 85%, respectively, based on observed cases.Citation34 WELCOME trial with 539 patients either intolerant or poor responders to infliximab, which was given open-label induction, showed 62% response rates and 39.3% remission rates, despite being a difficult-to-treat group.Citation35
Side effects
The common adverse effects include injection site reactions and infections mainly of the respiratory tract and urinary tract; some of which can be very severe due to immune modulation. Similar to the other drugs in the class, reactivation of tuberculosis, hepatitis B, and malignancies have been reported, but hypersensitivity reactions are rare.Citation36 Some of the other rare adverse effects reported in controlled trials are blood dyscrasias, optic neuritis, hepatitis, alopecia totalis, anxiety, bipolar disorder, suicidal tendencies, nephrotic syndrome, renal failure, menstrual disorders, and dermatitis.Citation29 Certolizumab is a category B drug in pregnancy. Animal studies have proven no harm, but controlled human studies are not done.Citation29 Because of its large molecular weight, it neither crosses the placental barrier nor gets secreted in the milk. Even if present in milk, the biologics would get degraded in the intestinal tract, but the local effect in the mucosa is not known.Citation29 It is not recommended in pediatric use, and caution should be excised regarding its use in elderly due to the risk of malignancy and opportunistic infections.Citation29
Golimumab (Simponi®)
Mechanism of action and indications
Golimumab is yet another fully human IgG1 kappa MAb first approved in 2009 by FDA for the treatment of RA. It was developed and marketed by Janssen Biotech, Inc (Horsham, PA, USA).Citation37 It was isolated from a hybridoma clone produced by transgenic mice, which were immunized with human TNF-α. The commercial product, which is produced in a recombinant cell line culture, binds to the soluble and transmembrane forms of TNF-α and acts as an inhibitor.Citation38 This agent has been approved for use in moderately to severely active RA, psoriatic arthritis, ankylosing spondylitis, and moderately to severely active UC.Citation39 The European Medicines Agency has further approved it for JIA in combination with methotrexate for children >40 kg body weight.Citation40 It is available as prefilled glass syringes (27G 1/2 in) providing either 50 mg/0.5 mL or 100 mg/1 mL of solution.Citation39 Upon SC administration, the bioavailability was 53% and gets primarily distributed in the circulatory system with limited extravascular distribution.Citation39 The terminal plasma half-life is ~2 weeks, and the metabolic pathway is not known.Citation39
Dosing in UC
The recommended dosage regimen for UC is 200 mg SC at week 0 followed by 100 mg at week 2 and maintenance therapy 100 mg once every 4 weeks.Citation39 in the PURSUIT-SC, a Phase II/III multicenter, placebo-controlled, induction RCT, anti-TNF-naive patients with moderately to severely active UC were assigned randomly to receive placebo, or two golimumab regimens were given 2 weeks apart (200 mg followed by 100 mg or 400 mg followed by 200 mg). At week 6, both the golimumab regimens induced significant clinical response (30 versus 51 and 55%, both P<0.0001) and clinical remission (6 versus 18 and 18%, both P<0.0001).Citation41 In the PURSUIT-M RCT, patients in clinical response were randomized to receive either placebo or two regimens of golimumab (50 or 100 mg every 4 weeks) for 52 weeks. At week 54, patients on golimumab achieved more continuous clinical response (31 versus 47 and 50%, P=0.01 and <0.001) and remission (16 versus 23 and 28%, P=0.12 and 0.004).Citation42
Side effects
The common adverse events noted were infections and injection site reactions, which were similar in number to the placebo arm.Citation43 Golimumab as the other TNF-α inhibitors can rarely cause severe infections, opportunistic infection, reactivation of tuberculosis, malignancies, heart failure, autoimmunity, and demyelinating disorders.Citation43 It belongs to a category B drug in pregnancy as animal studies have shown no harm, but controlled human studies are lacking.Citation39 The information regarding secretion into human milk, the effect on breastfed infant, or lactation is not known.Citation39 Efficacy in children is not well established with one study on pediatric juvenile idiopathic arthritis demonstrating no efficacy but similar rate of adverse events when compared with adults.Citation44 Caution should be exerted while using in elderly due to increased risk of infections and malignancy with increasing age.Citation39
Infliximab (Remicade®)
Mechanism of action and indications
Infliximab is an engineered chimeric IgG1 MAb and created by combining mouse and human TNF that has increased the specificity and affinity to the TNF-α receptor. In 1988 at New York University’s School of Medicine, this MAb against TNF has been discovered.Citation45 Remicade was the first TNF-α blocking agent approved by the FDA, initially for treating CD, in 1998. This is produced when the variable regions of a murine antibody (25%) are fused with the constant regions of a human antibody (75%) at the hinge region using genetic engineering.Citation46 It is indicated for use in CD (pediatric and adult), UC (pediatric and adult), RA, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.Citation47 The agent is supplied as a sterile, white, lyophilized 100 mg powder for IV infusion in a 20 mL vial. Each single-dose vial contains infliximab (100 mg), dibasic sodium phosphate dehydrate (6.1 mg), monobasic sodium phosphate, monohydrate (2.2 mg), polysorbate 80 (0.5 mg), and sucrose (500 mg) and no preservatives.Citation47 In adults, single IV infusion of 3–20 mg/kg showed a linear relationship between the dose that was administered and the maximum serum concentration.Citation47 It acts by inhibiting the binding of TNF-α with its receptors. This results in the induction of proinflammatory cytokines such as IL-1 and IL-6. This causes an enhancement of leukocyte migration by increasing endothelial layer permeability and the expression of adhesion molecules by endothelial cells and leukocytes and results in the activation of neutrophil and eosinophil functional activities and the induction of acute-phase reactants and other liver proteins, as well as tissue-degrading enzymes produced by synoviocytes and/or chondrocytes.Citation47 Infliximab does not neutralize TNF-β, and the median terminal half-life of infliximab is 7.7–9.5 days.Citation47
Dosing in CD and UC
The recommended dose is 5 mg/kg at 0, 2, and 6 weeks, which is followed by the maintenance regimen of 5 mg/kg every 8 weeks after that for the treatment of CD or UC in both adults and children.Citation47 For adult patients with CD who respond and then lose their response, consideration may be given to treatment with 10 mg/kg.Citation47 In the Targan study, 65% of patients with active CD had a clinical response at weeks to doses 5, 10, and 20 mg/kg versus 17% for placebo with no dose–response effect. The remission rates were 33 versus 4%. In the ACCENT-1 trial with 573 patients and dose of 5 mg/kg, 58% achieved a clinical response and 28% achieved remission at week 2. It was also found that three loading doses at weeks 0, 2, and 6 had significantly higher response rate at week 10 when compared with a single infusion at week 0 (69 versus 59%, P=0.035).Citation48 In the ACCENT-1 maintenance trial, all patients received an induction dose of 5 mg/kg infliximab IV and then they were randomized to receive placebo or infliximab two doses (5 or 10 mg/kg) for 1 year once every 8 weeks. The proportion of patients who had remission at 2 weeks and continued to be in remission at 30 weeks was 21%, 44%, and 45%.Citation49 The evidence for the usefulness of infliximab in UC was mainly by two RCTs namely ACT-1 and ACT-2.Citation50 In ACT-1, 69% and 62% of patients who received infliximab 5 and 10 mg/kg, respectively, at weeks 0, 2, and 6, had desired clinical response at week 8, in comparison to 37% of those receiving placebo (P<0.002 for both comparisons).Citation51 In ACT-2, 65% and 69% of patients who received infliximab 5 and 10 mg/kg, respectively, achieved a clinical response at week 8, when compared with 26% of those receiving placebo (P<0.001 for both comparisons).Citation52 A study done by Cote-Daigneault et al has shown the evidence for efficacy in fistulizing CD and achieving mucosal healing in CD unlike certolizumab and in UC.Citation23
Side effects
The main adverse effect includes the development of antibodies that may lead to the loss of response, infusion reactions, and serum sickness-like reactions.Citation50 Problems associated with immunomodulation as easy susceptibility to infections, reactivation of tuberculosis, certain malignancies, and opportunistic infections are similar as in other TNF-α inhibitors.Citation50 There have also been reports of hepatitis, CNS vasculitis, and hematological derangements that have been reported with the use of infliximab.Citation47 This agent belongs to category B in pregnancy, and its effect on a lactating infant or its presence in human milk is not known. However, as in other IgG antibodies, it is present in the placenta and the new born may face difficulties with immune suppression.Citation47 Its safety and efficacy has been well established in children older than 6 years for use in UC and CD. Use of infliximab in elderly is advised with caution due to an otherwise increased risk of malignancy and infections.Citation47
Integrin receptor antagonists
Vedolizumab (Entyvio)
Mechanism of action and indications
Vedolizumab is a humanized MAb, which was approved by the FDA in July 2014 after a priority review. It is essentially an integrin α4β7 receptor antagonist, which blocks the binding of Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) to the integrin receptor, thereby producing anti-inflammatory action by preventing T-cell adhesion and infiltration.Citation53 Since integrin α4β7 receptors are found more in the gut epithelium, vedolizumab is indicated currently for moderate-to-severe CD and UC.Citation54 Clinical trials in pediatric population are also ongoing for UC and CD since November 2017.Citation55,Citation56 The agent is available in the market as 300 mg of lyophilized cake in a single-dose 20 mL vial for reconstitution.Citation57 The plasma half-life is ~25 days. The drug undergoes a rapid, saturable, and nonlinear elimination at low concentration and a slower, linear, and nonspecific elimination at therapeutic or higher concentration.Citation57
Dosing in CD and UC
Vedolizumab is given as a 300 mg IV infusion at 0, 2, and 6 weeks and then every 8 weeks after that, for both UC and CD. If no improvement is noticed, the drug is withdrawn.Citation57 In the GEMINI I induction therapy trial, 374 UC patients received either vedolizumab 300 mg (n=224) or only placebo (n=149) IV at weeks 0 and 2. The rates of clinical response (47% versus 26%) and clinical remission (17% versus 5%) at week 6 were statistically significant (P<0.001 for both).Citation58 Those with clinical response at week 6 were randomized to receive vedolizumab 300 mg IV every 4 weeks, or every 8 weeks or placebo for 52 weeks. The rates of clinical remission were 45% for the vedolizumab 4-weekly group, 52% for the vedolizumab 8-weekly group, and 16% for the placebo group (P<0.001).Citation58 The CD trials included the GEMINI II and GEMINI III, which showed mixed results of efficacy.Citation59 At week 6 in GEMINI II RCT, clinical remission was seen in 14.5% who received vedolizumab and 6.8% who received placebo and clinical response was seen in 31.4% who received vedolizumab and 25.7% who received placebo (P=0.23). Among patients who responded to induction therapy, 39.0% and 36.4% of those who received vedolizumab 8- and 4-weekly, respectively, were in clinical remission at week 52% versus 21.6% of those who received placebo (P<0.001 and 0.004, respectively, for the two vedolizumab groups versus placebo).Citation60 GEMINI III trial was conducted in patients with TNF antagonist failure, and the remission rates at week 10 were 26.6% in vedolizumab group versus 12.1% in placebo group (nominal P=0.001). The response rates at week 6 were 39.2% versus 22.3%, respectively (nominal P=0.001).Citation61
Side effects
The most common adverse reactions seen with vedolizumab are infusion reactions and infections due to immunomodulation.Citation54 Safety data showed a similar adverse reaction rate to placebo.Citation55 Malignancies were reported in 0.4% of those treated with vedolizumab, but the long-term exposure was limited.Citation57 A potential for immunogenicity was found with 13% of the patients treated showing antivedolizumab antibodies at 24 weeks.Citation57 Safety and effectiveness in the pediatric population have not been established, while in geriatric population, no difference in safety and efficacy has been observed compared to the adult population.Citation57 Till date, no studies have been done with this drug in pregnant women and it is rated a category B drug.Citation57 No fetal harm was observed in studies done on rabbits and monkeys even at 20 times the recommended human dosage.Citation57 Animal studies detected vedolizumab in the milk of lactating monkeys, but it is still unknown whether it can be generalized to humans. Hence, the drug should be used with caution in nursing mothers.Citation57
Natalizumab (Tysabri®)
Mechanism of action and indications
Natalizumab, the first among its drug family, is a humanized IgG4 MAb against the α4 chains of integrins and behaves as a selective adhesion molecule antagonist inhibiting the translocation of leukocytes across blood vessel membranes approved by FDA in year 2004.Citation62 The agent is nonspecific to antagonize α4β1 integrin (very late antigen [VLA]-4) and the α4β7 integrin (lymphocyte Peyer’s patch adhesion molecule [LPAM]-1).Citation63 VLA-4 is involved in regulating the trafficking of mononuclear leukocytes from the peripheral circulation to sites of inflammation, and this mechanism is tapped to treat multiple sclerosis.Citation63 The only other indication of use is in CD, and the mechanism of action is similar to vedolizumab.Citation63 It is available as 300 mg natalizumab in 15 mL (20 mg/mL) IV solution in a sterile, single-use vial with no preservatives.Citation64 Upon administration, the number of circulating leukocytes of all types is increased except the absolute neutrophil count.Citation64 The mean half-life was ~10–11 days, and a steady state concentration after a 4-weekly dose was achieved at 24 weeks.Citation64
Dosing in CD
The recommended dose in CD is 300 mg IV infusion over 1 hour 4-weekly, and the agent was discontinued at 12 weeks if no response. It should not be used with concomitant immunosuppressants (eg, 6-mercaptopurine, azathioprine, cyclosporine, and methotrexate) or concomitant inhibitors of TNF-α.Citation64 ENACT-1 trial with 905 adult patients with moderate-to-severe disease across 142 global centers proved the efficacy of natalizumab in CD. Patients randomly received 300 mg natalizumab 4-weekly (n=721) or placebo (n=181), and clinical response at week 10 was 56% versus 49% (P=0.05), respectively, while remission was seen in 37% versus 30% (P=0.12), respectively.Citation65 Those with clinical response at week 10 underwent the maintenance phase for 52 weeks, and the sustained response was 61% versus 28% in placebo arm (P<0.0001).Citation65 The next landmark trial was the ENCORE trial where 509 adult patients were randomized to receive natalizumab or placebo. At week 12, the clinical response rate was 60% versus 44% (P=0.001) and the remission rates were 38% versus 25% (P=0.001), respectively.Citation66
Side effects
The most common adverse effects encountered are a headache, abdominal pain, joint pain, colitis including worsening of CD, influenza syndrome, infection, gastrointestinal disturbances, fatigue, pharyngitis, and infusion reaction.Citation67 The serious adverse reactions as listed by the FDA include progressive multifocal leukoencephalopathy due to infection with John Cunningham virus, Herpes infections, hepatotoxicity, hypersensitivity, antibody formation, and immunosuppression.Citation64 Natalizumab is a category B drug in pregnancy with detection in human milk as well, though its effect on a breastfed infant is unknown.Citation64 It is not recommended for use in children, and sufficient data are not available to identify difference in responses among elderly.Citation64
IL-12 and IL-23 antagonist
Ustekinumab (Stelara®)
Mechanism of action and indications
Ustekinumab is a human IgGIκ MAb against the p40 subunit of IL-12 and IL-23 cytokines. It was first approved in Canada in 2008 for the treatment of plaque psoriasis in adult patients and later in 2009 by FDA.Citation68 IL-12 and IL-23 play an important role in the activation and differentiation of natural killer cells and CD4+ T lymphocytes. Hence, blocking their action helps in chronic inflammatory conditions such as plaque psoriasis, psoriatic arthritis, and CD.Citation69 It is available as IV 130 mg/26 mL (5 mg/mL) solution in a single-dose vial and SC 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe or 45 mg/0.5 mL in a single-dose vial.Citation70 Treatment has been shown to decrease the expression of mRNA of IL-12 and IL-23. Steady-state concentrations are achieved by week 28, and the mean elimination plasma half-life ranges from 15 to 45.5 days.Citation70
Dosing in CD
The recommended dosage regimen is a single IV dose, which is weight based (260 mg if weight is ≤55 kg, 390 mg if weight is >55–85 kg, and 520 mg if weight is >85 kg) followed by a maintenance dose of SC 90 mg administered 8-weekly.Citation70
The safety and efficacy of ustekinumab were evaluated in three randomized double-blind placebo-controlled clinical namely UNITI-1 and UNITI-2 for induction therapy and IM-UNITI for maintenance therapy.Citation68 In the UNITI-1 trial (n=741), the clinical response rate at week 6 was 33.7% and 21.5% (P<0.01) and the remission rate at week 8 was 20.9% and 7.3% (P<0.001) in the ustekinumab and placebo arms, respectively.Citation71 In the UNITI-2 trial (n=628), the clinical response rate at week 6 was 55.5% and 28.7% (P<0.001) and the remission rate at week 8 was 40.2% and 19.6% (P<0.001) in the ustekinumab and placebo arms, respectively.Citation71 IM-UNITI trial testing ustekinumab 90 mg SC maintenance 8-weekly and 12-weekly, 53.1% and 48.8%, respectively, were in clinical remission at week 44 when compared with 35.9% receiving placebo (P=0.005 and 0.04, respectively).Citation72
Side effects
The most common adverse effects encountered were nasopharyngitis, injection site erythema, and vulvovaginal candidiasis besides other infections. Clinically significant and serious infections included anal abscess, gastroenteritis, and pneumonia.Citation69 A total of 0.2% of ustekinumab-treated patients and placebo-treated patients developed NMSC, whereas 0.2% of the ustekinumab-treated patients developed other cancers, which were none in the placebo group.Citation70 Approximately 6% of the patients in the psoriasis studies developed antiustekinumab antibodies whereas only 3% of the patients in the CD studies did so.Citation70 During the postmarketing phase, more incidents of hypersensitivity reactions such as anaphylaxis, angioedema, rashes, and urticaria have been reported.Citation70 Human data on effects in pregnancy are not well established due to the lack of data. Animal studies have not shown any adverse developmental effects on the fetus even at doses >100 times the recommended human dose.Citation70 Though studies in lactating monkeys have shown the presence of ustekinumab in the milk, no presence of the drug in human milk has been found.Citation70 Safety and efficacy have not been established in the pediatric population, and there are no enough data among elderly to determine any difference in the safety and efficacy as compared to the adult population.Citation70
Biosimilars in IBD
The treatment of IBD imposes a tremendous economic burden on the health care system as the cost utilization has seen a significant shift from hospitalization to medication, especially the biologics.Citation73 With the patent period of many of these drugs coming to an end, it is possible to produce a similar biologics that could be marketed at a much lower price than the innovator biologics, some of which are already available in developing countries such as India and developed countries such as South Korea.Citation74 These drugs are called as biosimilars, which may be defined as a biologic product that is highly like the reference biologic with no clinically meaningful differences in clinical safety or efficacy.Citation75 Biologics are a highly complex protein or other substances derived from a biological source, and hence, complete reproducibility of reference biologics is not possible. Thus, minor differences in clinically inactive components are permissible.Citation76 The current biosimilars approved for use in IBD belong to TNF-α inhibitors namely adalimumab and infliximab.Citation77 Biosimilars of adalimumab include adalimumab-atto (Amjevita™) by Amgen Pharmaceuticals (Thousand Oaks, CA, USA) and adalimumab-abdm (Cyltezo®) by Boehringer Ingelheim. Amjevita was created using recombinant DNA technology in a mammalian cell expression system resulting in an antibody with human IgG1:k constant regions and human-derived heavy- and light-chain variable regions. It was approved by FDA in September 2016.Citation78 Cyltezo is again a recombinant human IgG1 MAb, which was approved in August 2017.Citation79 The indications of these two agents are similar to Humira except in hidradenitis suppurativa and uveitis in the same dosage regimen with similar efficacy and side effects.Citation78,Citation79
With regard to infliximab, there are again three biosimilars, which are approved by FDA namely infliximab-dyyb (Inflectra®) by Pfizer (New York City, NY, USA), infliximab-abda (Renflexis™) by Samsung Bioepis (Seoul, South Korea), and infliximab-qbtx (Ixifi™) by Pfizer in 2016, 2017, and 2017, respectively.Citation80–Citation82 Both chimeric IgG1κ MAb composed of human constant and murine variable regions, which are produced by a recombinant cell line cultured.Citation80,Citation81 These agents are used in the same indications as Remicade at same dose with similar efficacy and adverse effects.Citation80,Citation81
Future paradigm
Biologics off late as mentioned has become an important modality of treatment in IBD and the mainstay of therapy in patients with fistulizing or perianal CD.Citation83 However, the available treatment has certain drawbacks, the most important of which is 30% primary nonresponders.Citation84 Some patients transiently show response but then experience a loss of response (secondary nonresponders).Citation85 Besides this, the available agents come with a myriad of serious adverse effects such as antibody formation, malignancies, reactivation of tuberculosis and hepatitis B as mentioned. Therefore, there is a need to develop newer agents that are more effective with fewer side effects and agents with novel targets and novel mechanisms of action. Some of these novel targets include Janus kinase inhibitors (eg, tofacitinib), IL inhibitors, antisense oligonucleotides (eg, mongersen), sphingosine-1-phosphate (S1P) receptor agonist (eg, ozanimod), anti-integrin inhibitors, and so on.Citation86 Janus kinase inhibitors interfere with the signaling pathway that is needed for inflammatory process, whereas the antisense oligonucleotides prevent translation process by binding to mRNA from which the protein is usually synthesized.Citation87,Citation88 S1P receptor agonists decrease the total lymphocyte count in circulation, especially CD4+CCR7+ and CD8+CCR7+ T cells.Citation89
Conclusion
As the burden of IBD is increasing with time, so is the plethora of novel agents under development for its treatment. Initially, biologics were prescribed much later in the course of the disease, but this paradigm has changed with the increasing availability of evidence that suggests early use of biological agents. Also, the focus of treatment has shifted from mere supportive or symptomatic to more therapeutic or curative. One of the significant hurdles faced currently with these newer biologics is the cost and adverse reactions. With the availability of biosimilars in the market now, the cost has come down drastically, and in the future with novel agents in the pipeline, one could expect to see agents with enhanced safety and tolerability.
Author contributions
All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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