A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis

Abstract

Objective: To evaluate the safety and efficacy of an enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule, after 1, 3, and 6 months. Methods: This was a randomised, placebo controlled, double blind, escalating dose multicentre study in 40 patients with mild to moderately active distal ulcerative colitis (disease activity index (DAI) 4-10). Patients were assigned to four dosing cohorts of 10 patients each (eight active, two placebo). Each patient received 60 ml of alicaforsen enema (0.1, 0.5, 2, or 4 mg/ml or placebo) once daily for 28 consecutive days. Safety and efficacy (DAI and clinical activity index) scores were evaluated up to six months after initiation of dosing. Results: At day 29, alicaforsen enema resulted in dose dependent improvement in DAI (overall p = 0.003). Alicaforsen 4 mg/ml improved DAI by 70% compared with the placebo response of 28% (p = 0.004). Alicaforsen 2 and 4 mg/ml improved DAI status by 72% and 68% compared with a placebo response of 11.5% at month 3 (p = 0.016 and 0.021, respectively). Specifically, DAI improved from 5.6 to 1.6 and from 6.3 to 2.5 in the 2 and 4 mg/ml groups compared with placebo (7.5 to 6.1). None of the patients in the 4 mg/ml group compared with 4/8 placebo patients required additional medical or surgical intervention over baseline during the six month period after starting the enema treatment. The safety profile was favourable. Conclusions: Alicaforsen enema showed promising acute and long term benefit in patients with mild to moderate descending ulcerative colitis. Alicaforsen enemas had a favourable safety profile. These findings require verification in larger randomised controlled clinical trials.

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

“…Our results with a clear and fast reduction of clinical disease activity (Mayo score -27%, partial Mayo score -60%, and 6-point symptom score -62%) are consistent with those of the open label study by Miner et al [27] and the small randomized-controlled trial by van Deventer [28]. The clinical improvement rate of 83.3% (10 out of 12) is comparable to that of Miner et al [27] (clinical improvement in 12/15 patients [80%]).…”

“…Nonetheless, a prolonged clinical response was observed in both trials with a significant reduction in dis-Dig Dis 2018;36:123-129 DOI: 10.1159/000484979 ease activity at weeks 18 and 30 compared to placebo (51 vs. 18% and 50 vs. 11%) and a significant longer duration of response compared to mesalazine (146 vs. 54 days). In a smaller randomized controlled trial, van Deventer et al [28] showed both a short-term and long-term benefit from alicaforsen enema treatment: disease activity was reduced by 78% at day 29 and by 68% at 3 month compared to a placebo response of 28 and 11.5% respectively. Given the fact that the half-life period of alicaforsen is only 24 h, these findings have led to the concept of a disease-modifying ef- fect.…”

Intercellular Adhesion Molecule-1 Deficiency Attenuates the Development of Skin Fibrosis in Tight-Skin Mice

“…Therefore, antisense oligonucleotides represent a strategy for modulating cell adhesion by inhibiting the expression of adhesion molecules. Clinical trials of ICAM-1 antisense oligonucleotides have already been started in human inflammatory bowel diseases (58,59) and rheumatoid arthritis (60). Until now, few therapies have proved to be effective for SSc in control studies.…”

New Biologic Drugs for Ulcerative Colitis

“…Initial positive results in CD patients reported in a pilot study were not confirmed in two subsequent placebo controlled trial (45)(46)(47). Instead in a placebo controlled trial with ISIS 2302 in enema formulation showed significant improvement in 40 patients with distal UC (48). In a phase 2, dose-ranging, double-blind, placebo-controlled study, 112 patients with mild-moderate left-sided UC received one of four ISIS 2302 enema regimens or placebo daily for 6 weeks (49).…”