Alicaforsen
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.
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.[1] 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.[1] Alicaforsen works by binding to the section of messenger RNA that encodes for ICAM-1, and also by degrading ICAM-1 (through an RNase-H based mechanism).[1] 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 was licensed by Atlantic Healthcare Ltd from ISIS Pharmaceuticals in 2007.[2][3] Alicaforsen enema has undergone four Phase II studies in ulcerative colitis and a confirmatory proof of principal study in chronic, unremitting pouchitis.[4][5][6][7][8] Randomised and controlled Phase II studies suggest that alicaforsen brings 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.[6]
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). It is granted to encourage development of drugs for the treatment of rare diseases and conditions where there are low numbers of patients and where it would otherwise be prohibitively expensive or unprofitable for a company to do so.[2][3] The FDA has granted Fast Track Approval to alicaforsen for the treatment of chronic and recurrent pouchitis in recognition of unmet need.[2][3]
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).[2][3]
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.[9]
References
- ^ a b c Miner, PB Jr (2006). "Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis". Alimentary Pharmacology & Therapeutics. 23: 1427–1434. doi:10.1111/j.1365-2036.2006.02909.x.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b c d "Severe and Rare". Isis Pharmaceuticals. Retrieved 31 August 2013.
- ^ a b c d "The FSE Group". Retrieved 2012-09-26.
- ^ Miner, PB Jr (2006). "Safety and Efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial". Alimentary Pharmacology & Therapeutics. 23: 1403–1413. doi:10.1111/j.1365-2036.2006.02837.x.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Miner, PB Jr (2006). "Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjcts with active ulcerative colitis". Alimentary Pharmacology & Therapeutics. 23: 1427–1434. doi:10.1111/j.1365-2036.2006.02909.x.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b Van Deventer, SJH (2006). "A Phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided colitis". Alimentary Pharmacology & Therapeutics. 23: 1414–1425. doi:10.1111/j.1365-2036.2006.02910.x.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Miner, PB Jr (2004). "An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis". Alimentary Pharmacology & Therapeutics. 19: 281–286. doi:10.1111/j.1365-2036.2004.01863.x. PMID 14984374.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Van Deventer, SJH (2004). "A Randomised, controlled, double blind, escalating dose study of alicaforsen enemain active ulcerative colitis". Gut. 53: 1646–1651. doi:10.``36/gut.2003.036160.
{{cite journal}}: Check|doi=value (help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Vegter, S; Tolley, K; Wilson Waterworth, T; Jones, H; Jones, S; & Jewell D (2013) "Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatmenet of active ulcerative colitis". Alimentary Pharmacology and Therapeutics 38: 284-293 doi:10.1111/apt.12369