Alicaforsen, an Antisense Inhibitor of Intercellular Adhesion Molecule-1, in the Treatment for Left-Sided Ulcerative Colitis and Ulcerative Proctitis

Abstract

Background: Data on the efficacy of intercellular adhesion molecule-1 antisense oligonucleotide alicaforsen in ulcerative colitis (UC) is inconsistent. Methods: All patients, who had received at least one dose of alicaforsen, were analyzed retrospectively. Alicaforsen’s efficacy was assessed in patients treated for left-sided UC and proctitis by comparing clinical and (if applicable) endoscopic disease activity before/after treatment. Results: Twelve patients were treated for left-sided UC or proctitis. Eleven patients received a 6-week course of a once-daily 240 mg alicaforsen enema formulation. In 1 patient, treatment was discontinued, because it was found to be inefficient. Disease activity measured by the partial Mayo score and 6-point symptom score was significantly reduced after treatment (6.0 vs. 2.4, p = 0.011 and 3.7 vs. 1.4, p = 0.008). Faecal calprotectin showed a trend towards reduction (484.4 vs. 179.5 μg/g, p = 0.063). Clinical improvement was achieved in 10 patients (83.3%). In 7 patients, a relapse occurred (70%). Median duration of clinical improvement was 18.0 weeks (range 1–112). Three patients showed an ongoing improvement of >9 months. No adverse events were reported. Conclusions: A 6-week course of alicaforsen seemed to be safe and efficacious in inducing clinical improvement in patients with left-sided UC and proctitis. Prolonged clinical improvement was observed in many but not all patients.

Mesyl phosphoramidate antisense oligonucleotides as an alternative to phosphorothioates with improved biochemical and biological properties

“…The toxicity of PS-AONs in vivo has been an important issue, however. Alicaforsen (ISIS 2302), a 20-nt PS ODN complementary to a part of the human intercellular adhesion molecule-1 mRNA (18), has been studied extensively as an enema-applied treatment for ulcerative colitis (19), inflammatory bowel disease (20), and pouchitis (21). Identified problems included immune stimulation (mice, 20 mg/kg) (22), increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in serum suggestive of hepatic damage (mice, 100 mg/kg) (23), lethargy, changes in blood clotting time and atrophic processes in kidneys (monkeys, 10 mg/kg) (24), and red blood cells in the renal lumen (monkeys, 50 mg/kg) (25, 26).…”

The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease

“…This a4 integrin antagonist could also induce clinical remission in patients with UC but not with CD [151,152]. Furthermore, alicaforsen, a synthetic antisense oligonucleotide against the adhesion molecule ICAM-1, proved to be effective in patients with UC in phase 2 trials and especially in patients with UC-related pouchitis in phase 3 trials [153][154][155][156][157][158][159][160], whereas in patients with CD, alicaforsen did not significantly improve the clinical outcome [161][162][163][164][165]. Additionally, it was observed that a telluriumbased compound could preserve the colonic epithelium integrity in the DSS colitis mouse model by preventing the migration of a4β7 + macrophages to the colon and the adhesion of MLN cells to MadCAM-1 both in vitro and in vivo.…”

Emerging therapeutic options in inflammatory bowel disease

“…The most frequent adverse events were asthenia, infections, and nausea. No serious adverse events related to the medical treatment[ 124 ]. In another phase 2 clinical trial, no significant difference was observed between treatment arms and placebo in the primary endpoint[ 125 ].…”