Table 1.
Overview of clinical studies with alicaforsen.
| Study drug | Study | Phase | Study population | Study design | Cohort size | Drug dosage and frequency of doses | Primary endpoint | Results |
|---|---|---|---|---|---|---|---|---|
| ISIS 2302 | Phase I safety and pharmacokinetic profile of an intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302) (Glover et al., 1997) | Phase 1 | Healthy male volunteers | Double-blind, placebo-controlled study | 44 male volunteers | Four healthy male volunteers recruited to each of seven single-dose groups (0.06, 0.12, 0.24, 0.5, 1.0, 1.5, and 2.0 mg/kg) and each of four multiple-dose groups (0.2, 0.5, 1.0, and 2.0 mg/kg). One subject in each group was allocated to placebo arm. The drug was infused intravenously on day 1 in the single dose-group and on days 1, 3, 5, and 7 in the multiple-dose group | Safety and pharmacokinetic profile of the drug | Good tolerability to the drug, with reproducibility of plasma pharmacokinetics |
| ISIS 2302 | Dose ranging pharmacokinetic trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn's disease (Yacyshyn et al., 2002a) | / | Patients with active CD (CDAI ≥220) | Double-blind, randomized study | 22 CD patients | 10 patients were randomized to the 300 mg arm, 10 to the 350 mg arm and 2 patients to the 250 mg arm. The drug was infused intravenously three times a week for 4 weeks | Clinical remission (CDAI ≤ 150) at week 8, 12, and after 6 months | In the intention to treat (ITT) population 14% (3/22) of the patients at week 8 and 23% (5/22) of the patients at week 12 were in clinical remission. After 6 months, 18% (4/22) of the ITT patients were in clinical remission. The efficacy was equivalent with all the three doses used |
| ISIS 2302 | A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease (Yacyshyn et al., 1998) | / | Patients with active moderate CD (CDAI 220–350) | Double-blind, placebo-controlled study | 20 CD patients | The patients were randomized (3:1, ISIS 2302 to placebo). The drug was infused intravenously at a dosage of 0.5, 1, or 2 mg/kg and was administered in 13 doses over 26 days | Assessment of tolerability, pharmacology and efficacy of the drug in steroid-dependent CD | Clinical remission was figured out in 47% (7/15) of the patients treated with the drug and in 20% (1/5) of those treated with placebo after 26 days from the start of the therapy. After 6 months 5 of the 7 patients treated with the drug maintained remission. The drug was correlated to a good profile of safety |
| ISIS 2302 | Efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease (Schreiber et al., 2001) | / | Patients with steroid-refractory CD (CDAI 200–400) | Double-blind, placebo-controlled study | 75 CD patients | 75 patients were randomized to 4 treatment arms and a placebo group. 14 patients received treatment for 2 days, 17 patients for 1 week, 15 patients for 2 weeks and 14 patients for 4 weeks. 15 patients received placebo. The drug was administered subcutaneously at a dosage of 0.5 mg/kg | Complete clinical remission (CDAI < 150 with discontinuation of steroids) at week 14 | Clinical remission was reached by 18.3% of treated patients and by 20% of those treated with placebo at the week 14. No difference in clinical remission between the drug and placebo was evidenced |
| ISIS 2302 | Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease (Yacyshyn et al., 2002b) | / | Steroid dependent CD patients with active disease (CDAI 200–350) | Double-blind, placebo-controlled study | 299 CD patients | The patients were randomized into three groups: ISIS 2302 at a dosage of 2 mg/kg intravenously three times a week for 2 weeks, ISIS 2302 at the same dosage and with the same frequency but for 4 weeks and placebo | Steroid free remission with a CDAI < 150 at the end of week 14 | Steroid free remission at week 14 was 20.2% in the group treated for 2 weeks, 21.2% in the group treated for 4 weeks and 18.8% in placebo group. No difference in clinical remission between the drug and placebo was evidenced |
| ISIS 2302 (Alicaforsen) | A randomized, double-masked, placebo-controlled study of alicaforsen, an antisense inhibitor of intercellular adhesion molecule 1, for the treatment of subjects with active Crohn's disease (Yacyshyn et al., 2007) | Phase 3 | Patients with active CD (CDAI 220–400) | Double-blind, placebo-controlled study | 331 CD patients | 221 patients were randomized to the study drug at a dosage of 100 mg at the first infusion and for the other 11 infusions at a dosage of 300 mg (patients weighing more than 50 kg) or 200 mg (patients weighing 36–50 kg). The drug was administered intravenously 3 times a week for 4 weeks. 110 patients were enrolled in placebo arm | Clinical remission at week 12 | No statistical difference between the study drug and placebo for clinical remission at week 12 (33.9% in the drug and 34.5% in the placebo arm) |
| ISIS 2302 (Alicaforsen) | A randomized, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis (van Deventer et al., 2004) | / | Patients with active distal UC (DAI 4–10) | Double-blind, placebo-controlled study | 40 UC patients | The patients were randomized to the alicaforsen enema administration at four different dosages (0.1, 0.5, 2, or 4 mg/ml) or to placebo. Each patient received alicaforsen enema once daily for 28 days | Safety and efficacy of the drug enema after 1, 3, and 6 months | At 1 month alicaforsen enema (4 mg/ml) was correlated with 70% of improved disease activity index compared to 28% with placebo, with statistical significant difference. This positive outcome was evidenced also after 3 and 6 months |
| ISIS 2302 (Alicaforsen) | A Phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis (van Deventer et al., 2006) | Phase 2 | Patients with active distal UC (DAI 4–10) with disease flare | Double-blind, placebo-controlled study | 120 UC patients | The patients were randomized to five treatment arms: placebo, alicaforsen enema at a dosage of 120 mg daily for 10 days and then every other day, 240 mg every other day, 240 mg daily for 10 days and then every other day, 240 mg daily | Disease Activity Index at week 6 | No significant difference between alicaforsen and placebo enema was evidenced at week 6, but the arm of alicaforsen (240 mg with daily administration) evidenced a statistical benefit over placebo for prolonged reduction of DAI from the week 18 to week 30 |
| ISIS 2302 (Alicaforsen) | 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 (Miner et al., 2006) | / | Patients with active UC (DAI 4–10) | Double-blind, active-controlled study | 159 UC patients | The patients were randomized to alicaforsen enema at a dosage of 120 mg or 240 mg or to mesalazine enema at a dosage of 4 g. The enema was administered daily for 6 weeks | DAI at week 6 relative to baseline | No difference in reducing clinical activity was evidenced between the treatment strategies at week 6, but alicaforsen enema evidenced more prolonged response than mesalazine enema |
| ISIS 2302 (Alicaforsen) | An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis (Miner et al., 2004) | / | Patients with chronic, unremitting pouchitis with a Pouchitis Disease Activity Index (PDAI) score of ≥7 | Open-label, uncontrolled study | 12 patients affected by chronic unremitting pouchitis | The patients received daily administration of alicaforsen enema at a dosage of 240 mg for 6 weeks | Efficacy of alicaforsen enema in the treatment of chronic unremitting pouchitis | A significant benefit of alicaforsen enema was evidenced at week 6. The PDAI score resulted to be 6.83 at week 6 compared to 11.42 at baseline. This benefit was evidenced also for improvement of endoscopic activity |
CD, Crohn's disease; UC, ulcerative colitis; CDAI, Crohn's disease Activity Index; DAI, Disease Activity Index; PDAI, Pouchitis Disease Activity Index; ICAM1, Intercellular Cell Adhesion Molecule-1; /, phase indication not found.