Etrolizumab is an investigational medication being studied for its potential to treat certain inflammatory conditions. This drug is a type of biologic therapy, specifically categorized as a humanized monoclonal antibody. Monoclonal antibodies are engineered proteins designed to target specific molecules in the body, and etrolizumab focuses on pathways involved in inflammation.
Targeted Mechanism
Etrolizumab targets specific proteins called integrins, found on immune cells. Specifically, it binds to the β7 subunit of both α4β7 and αEβ7 integrins. Integrins play a role in guiding lymphocytes to sites of inflammation, especially in the gut.
By blocking these integrins, etrolizumab interferes with the ability of certain immune cells to enter inflamed tissues. It prevents the α4β7 integrin from binding to MAdCAM-1 (mucosal vascular addressin cell adhesion molecule-1), a protein found on the lining of blood vessels in the gut. This action restricts the migration of lymphocytes from the bloodstream into the intestinal lining.
Additionally, etrolizumab blocks the interaction between αEβ7 integrin and E-cadherin, a protein found on epithelial cells lining the gut. This dual mechanism aims to control both the entry of immune cells into the gut and their retention within the intestinal mucosa, thereby reducing inflammation. Studies suggest that etrolizumab can induce the internalization of the β7 integrin, further impairing cell adhesion.
Primary Medical Application
Etrolizumab has been most extensively investigated for ulcerative colitis (UC). Ulcerative colitis is a chronic inflammatory bowel disease that primarily affects the large intestine, leading to inflammation and ulcers in the lining of the colon and rectum. Symptoms often include abdominal pain, bloody diarrhea, and urgency.
The drug aims to manage the inflammation and symptoms associated with UC by preventing the excessive migration of immune cells into the gut, which fuels the disease. This selective action helps to alleviate symptoms and promote healing of the inflamed intestinal lining.
Etrolizumab’s potential role in UC management is particularly relevant for patients who have not responded adequately to other treatments, such as TNF inhibitors or conventional therapies. Clinical trials have explored its efficacy in inducing and maintaining remission in individuals with moderate to severe UC.
Administration and Potential Side Effects
Etrolizumab is administered as a subcutaneous injection, meaning it is injected under the skin. In clinical trials, the dose was 105 mg, administered every four weeks. This method allows for patient self-administration at home following appropriate training.
Common side effects observed in clinical trials have been mild to moderate. Headache was reported as a common adverse event. Injection site reactions, such as redness or discomfort at the injection area, have also been noted, though serious injection site reactions were not frequently reported.
More serious but less common adverse events included exacerbations of ulcerative colitis. There were also instances of impaired wound healing post-colectomy in some patients, though these cases often involved confounding factors like high-dose steroids, low albumin, or other health conditions. The safety profile of etrolizumab showed no major safety issues identified in phase 3 clinical trials.
Current Research and Approval Status
Etrolizumab underwent a Phase 3 clinical trial program for ulcerative colitis and Crohn’s disease. This program included studies evaluating its efficacy and safety as both an induction and maintenance therapy. The trials involved over 3,000 patients across various populations, including those who had and had not previously received anti-TNF treatments.
However, ulcerative colitis results were mixed. While etrolizumab met its primary endpoint of inducing remission versus placebo in some induction studies, it did not consistently meet this endpoint in all induction studies or in maintenance therapy studies for UC. Following these mixed results, Hoffmann-La Roche, Genentech’s parent company, discontinued further development for ulcerative colitis in October 2020.
Development for Crohn’s disease continued, but also faced disappointing trial results, leading to discontinuation in February 2022. Therefore, etrolizumab is not currently an approved medication. It remains an investigational drug whose development for inflammatory bowel diseases has been paused.