CAS Number 185229-68-9 ChemSpider 17326145 Formula C192H244N75O98P19S19 | PubChem CID 16197724 ChEMBL CHEMBL2108326 | |
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Synonyms DNA, d[(R)-P-thio](G-C-C-C-A-A-G-C-T-G-G-C-A-T-C-C-G-T-C-A) | ||
Alicaforsen is an inflammatory bowel disease drug candidate. It is an antisense therapeutic that targets the messenger RNA for the production of human ICAM-1 protein. It is being progressed through clinical development as a nightly enema.
Contents
Structure and mode of action
Alicaforsen is a 20 unit phosphorothiate modified antisense oligonucleotide. It is designed to specifically inhibit and down-regulate at a cell level the production of human ICAM-1 protein. ICAMs are proteins that induce inflammatory responses in tissues in the body, including the gastro-intestinal tract. ICAM-1 propagates an inflammatory response, promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue. Alicaforsen works by binding to the section of messenger RNA that encodes for ICAM-1, and also by degrading ICAM-1 mRNA (through an RNase-H based mechanism). This causes a reduction in both ICAM-1 expression on cell surfaces and a selective reduction in ICAM-1 mRNA. In particular, it down-regulates ICAM-1 on vascular endothelial cells, inhibiting leucocyte adherence, migration and activation. In effect, alicaforsen is switching off the inflammatory process enabling tissue healing.
Clinical development
Alicaforsen (as intravenous injection) failed a phase III trial for Crohn's disease in 1999.
Randomised and controlled Phase II studies suggest that alicaforsen brings colitis patients in to and maintains them in remission with a durability between 128 and 146 days, demonstrating safety, efficacy and tolerability. This suggests that the drug may have a disease-modifying effect.
By 2006 Alicaforsen enema has undergone four Phase II studies in ulcerative colitis and a confirmatory proof of principal study in chronic, unremitting pouchitis.
Alicaforsen was licensed by Atlantic Healthcare Ltd from ISIS Pharmaceuticals in 2007.
In June 2008, Atlantic was granted orphan drug status for alicaforsen in the treatment of pouchitis in the USA by the US Food and Drug Administration (FDA). The FDA has granted Fast Track Designation to alicaforsen for the treatment of chronic and recurrent pouchitis in recognition of unmet need.
In April 2009, Atlantic was granted orphan drug status for the product in the treatment of pouchitis in Europe by the European Medicines Agency (EMA).
In 2013, a post hoc meta-anlysis using individual patient data from four Phase II studies in ulcerative colitis was published. It suggested that alicaforsen enema may offer an effective, potentially durable response in moderate to severe ulcerative colitis up to 40 centimeters from the anal verge. It also found that peak response to the drug occurred at 10 weeks, 4 weeks after final dosing.
In 2016 a phase 3 trial started for pouchitis.