Biologic Therapy of Ulcerative Colitis: Natalizumab, Vedolizumab, Etrolizumab (rHUMab Beta 7), Anti-MAdCAM

Fig. 45.1

Tc-99 m HMPAO WBC scintigraphy in a patient with ulcerative colitis (left) whole-body image and (right) a detail of the abdomen. Rapid migration of lymphocytes from the peripheral circulation to the colon is seen

Attempts to suppress inflammation in a gut-selective way have been successful with antibodies targeting alpha4 beta7+ T-lymphocytes, which have a phenotype of intestinal homing lymphocytes. This class of drugs is certainly anticipated to be superior from a safety perspective. Preclinical studies showed efficacy of blocking integrin α4(β7) in the spontaneous cotton-top tamarin colitis model [6, 7]. More recently, the genetic association between IBD and integrins (ITGAL = integrin alpha–L), chemokines and chemokine receptors has been uncovered. The main cell populations responsible for the adaptive immune response in the gut are antigen-presenting cells, which can be professional (dendritic cells) or not professional (epithelial cells), effector cells (effector T cells, granulocytes, natural killer, macrophages, etc.), regulatory T cells, and mucosal B cells. Secondary adhesion molecules are members of the family of integrins . These allow leucocytes to stop rolling and start migration and extravasation through the vascular wall. The expression of integrins is activated by chemokines, which are released by T cells. Integrins involved in the T-cell migration are as follows: leucocyte function-associated antigen 1 (LFA-1 or α2β2) and the two α4-integrins (α4β7 and α1β7). The subunit α is implied in the specificity and the subunit β in signal pathways. For the migration of the leucocytes, these integrins bind to specific ligands at the endothelium called addressins or adhesion molecules . The α2β2 integrin, expressed on neutrophils, interacts with intercellular adhesion molecule-1 (ICAM-1) that is expressed on leucocytes, dendritic cells, fibroblasts, epithelial cells, and endothelial cells. The α4β1 integrin is composed of one β1 chain and one α4 chain and is expressed on most leucocytes, but not on neutrophils. The α4β1 integrin binds to vascular cell adhesion molecule-1 (VCAM-1) and to components of the extracellular matrix such as fibronectin and thrombospondin. The third family is the α4β7 integrin, which is expressed on the lymphocytes that colonize the gut and gut-associated lymphoid tissues and interacts with the mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) . The MAdCAM-1 ligand is expressed in the endothelial venules in the small intestine, in the Peyer’s patches and the colon, and the interaction with integrin α4β7 activates the migration of lymphocytes to Peyer’s patches. Therefore, the interaction between α4β7 and MAdCAM-1 is gut-specific.

Natalizumab (Tysabri)

Anti-integrin strategies have been developed and two compounds have received FDA/EMA approval so far. Natalizumab, a human anti-alpha4 integrin antibody, was developed first and the clinical development with the ENCORE & ENACT trials met their primary endpoint [8, 9]. The drug received a FDA-fast track approval for treatment of moderate-to-severe Crohn’s disease, not responding to standard drugs. However, following a number of fatal case reports of patients treated with natalizumab who developed progressive multifocal leukoencephalopathy (PML) , a neurological disorder caused by reactivation of JC virus in the brain, further drug development was stopped [10, 11] (Fig. 45.2). In 2008, the US Food and Drug Administration (FDA) approved natalizumab (Tysabri) for the treatment of moderate-to-severe Crohn’s disease. Crohn’s disease patients who are started on Tysabri must be enrolled in a special restricted distribution program called CD TOUCH (Crohn’s Disease-Tysabri Outreach Unified Commitment to Health) . Under CD-TOUCH, physicians evaluate CD patients after 3 months of Tysabri treatment to determine if they have improved on Tysabri and if not, patients should discontinue further treatment. Previously, in 2006, Tysabri was approved by FDA to treat relapsing forms of multiple sclerosis.

Fig. 45.2

Brain MRI in a IBD patient treated with natalizumab shows progressive multifocal leucoencephalopathy (Van Assche G et al. N Engl J Med 2005;353:362–36)

Vedolizumab (Entyvio)

The necessity to develop a gut-selective drug became clear after reports of PML with the non-gut specific anti-alpha4 integrin natalizumab. Vedolizumab was developed soon after and inhibits the binding of alpha4beta 7 integrin to its receptor MadCam, hence selectively inhibiting homing of T-lymphocytes to the gut. Feagan et al. studied vedolizumab, in a randomized, double-blind trial of 29 patients with moderately severe UC [12]. Three single doses of vedolizumab 0.15, 0.5, and 2.0 mg/kg or placebo were studied. Follow-up studies looked at repeated doses: in the study by Feagan et al., 181 patients with active UC were randomized to receive vedolizumab 0.5, 2 mg/kg or matched placebo on days 1 and 29 [13]. The study by Parikh et al. included 47 patients and doses of 2, 6, 10 mg/kg or placebo, administered on days 1, 15, 29, and 85 [14]. The large GEMINI I phase III trial in UC was an integrated induction and maintenance study and met the primary endpoint of clinical response at week 6 [15]. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab at a dose of 300 mg or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2. In the trial of maintenance therapy, patients who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. At week 6, 47 % of UC patients treated with vedolizumab responded and 41 % showed healing (in contrast to 25 % for both endpoints in the placebo group). The long-term results were even more impressive as 45 % of patients treated with vedolizumab q4 weeks were in corticosteroid free remission at week 52 (14 % in the placebo arm) and 56 % had mucosal healing (20 % in the placebo arm). The GEMINI programs demonstrated superior efficacy in induction and maintenance of remission and in May 2014, vedolizumab was approved by FDA and also by the European Medicines Agency (EMA) for treatment of CD and UC [15, 16] (Fig. 45.3). An open-label GEMINI-long term safety (LTS) trial, is currently running and will be completed in March 2016 (NCT00790933).

Fig. 45.3

Endoscopic picture of patient with left-sided ulcerative colitis (left) shows endoscopic healing after treatment with vedolizumab (right)

Etrolizumab

Etrolizumab is a humanized IgG1 monoclonal antibody to β7 integrin expressed on lymphocytes. Etrolizumab inhibits therefore trafficking of T-lymphocytes into the gastrointestinal mucosa through interaction between alpha4 beta7 with MadCam but also blocks retention of lymphocytes in the gut epithelium by blocking interaction of alphaE beta7 and its ligand E-Cadherin. As such, etrolizumab is also gut-selective and does not interfere with leukocyte trafficking to the central nervous system or to other non-mucosal tissues and PML is also not expected to occur with this compound. The exact role of Alpha-E positive lymphocytes in human IBD is unknown and this cell population accounts for less than 1 % of all circulating lymphocytes in the peripheral blood.

A phase 1 study with etrolizumab showed a good safety profile [17]. The phase 2 study conducted in UC included 124 patients who were randomized to placebo or a low (100 mg) or high (300 mg + loading dose) of SC dosed etrolizumab q 4 weekly [18]. The primary endpoint was clinical remission at week 10. A significantly higher proportion of patients treated with etrolizumab low dose (21 %) or high dose + loading dose (10 %) met the primary endpoint of clinical remission compared to placebo (0 %). The effect was entirely driven by the anti-TNF naïve patient population, although the low sample size of this phase 2 study precludes from making strong statements about this observation. Interestingly, patients with high alpha-E (ITGAE) gene expression in their baseline colon biopsies had a higher likelihood of achieving clinical remission that patients with low alphaE gene expression (using a median cutoff value to define high and low expression). In addition a high numbers of αE+ cells predicted a higher remission rate. Based on these encouraging results, a large phase 3 program with etrolizumab is ongoing in anti-TNF naïve and experienced patients and includes besides placebo-controlled studies also a number of trial designs with active comparator arm against anti-TNF agents (e.g., NCT02136069, NCT02163759) (Fig. 45.4). Results are expected in 2017. The alpha-E positivity in the colonic biopsies will be checked to validate the findings of the phase 2 study on the role of alphaE as predictor of response.

Fig. 45.4

Endoscopic picture of patient with ulcerative colitis before (left) and after (right) treatment with etrolizumab

Anti-MadCam

Similar to inhibition of integrins expressed on gut lymphocytes, their respective ligands on the endothelial wall can also be the target. An anti-MadCam monoclonal antibody has been developed by Pfizer and a first-in-human study explored the safety and preliminary efficacy of this compound in ulcerative colitis (trial Register No. NCT00928681). A total of 80 patients with active UC received single or multiple (three doses, 4-week intervals) doses of anti-MadCam 0.03–10 mg/kg IV/SC, or placebo [19]. The overall responder/remission rates at 4 and 12 weeks were 52 %/13 % and 42 %/22 %, respectively with combined anti-MadCam doses compared with 32 %/11 % and 21 %/0 %, respectively with placebo. Clinical results were paralleled by a decrease in fecal calprotectin levels in patients treated with active drug compared to placebo. This led to the larger phase 2 study assessing different doses (7.5, 22.5, 75, or 225 mg) of anti-MadCam or placebo [20]. Primary endpoint was clinical remission at week 12 and was met for the 7.5, 22.5, and 75 mg doses, as compared to placebo. Interestingly, a bell-shaped dose-response curve was again seen with highest efficacy observed in patients receiving the 22.5 mg dose. This bell-shaped response curve was also observed in the etrolizumab phase 2 study where the low 100 mg dose showed superior results than the high 300 mg + loading dose group, and also in an early vedolizumab phase 2 study, the same observation was made. This poses the question if higher doses of drugs belonging to this mode of action, may also interfere with migration or activity of other cells such as regulatory T-cells? Another intriguing finding was the fact that the effect of anti-Madcam was observed almost exclusively in TNF-naïve patients, similar to what was seen with etrolizumab, and to a lesser extent with vedolizumab . If this represents a more refractory patient population is unclear at present.

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