Dose ranging pharmacokinetic trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn's disease.

Abstract

BACKGROUND AND AIMS:

To evaluate the safety, pharmacokinetics and clinical efficacy of the intercellular adhesion molecule-1 antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) at 250-350 mg in Crohn's disease.

METHODS:

: Patients (> 50 kg) with active Crohn's disease (Crohn's disease activity index > or = 220) were assigned by gender, randomly, to two alicaforsen treatment groups: 300 or 350 mg, infused intravenously three times a week for 4 weeks. All patients weighing 36-50 kg received 250 mg of alicaforsen. Background aminosalicylates, antibiotics, immunosuppressives and corticosteroids were permitted, but tumour necrosis factor-alphainhibitors were prohibited. The primary end-point was clinical remission (Crohn's disease activity index < or = 150).

RESULTS:

Twenty-two patients were enrolled with a mean baseline Crohn's disease activity index of 304. Steroids were used by 27%, 5-aminosalicylic acid by 68% and immunosuppressives by 27%; 23% had previously received infliximab. Five subjects withdrew after one to three infusions for infusion-related symptoms. Nine patients (41%) experienced clinical remission. Fifty-three per cent of the evaluable subjects receiving more than three infusions experienced remission (18% at week 8; 29% at week 12). The overall response, using a minimum decrease of 70 in the Crohn's disease activity index, was 41-47% for the evaluable group, at weeks 8 and 12. The median duration of remission was 14 weeks. Plasma pharmacokinetic results showed overlapping levels (Cmax, AUC) for the three doses. The infusion-related reaction profile consisted of fever, chills, headache, nausea, emesis or arthralgias, typically occurring 2-4 h after completion of the first infusion. Reactions were less frequent in patients receiving background corticosteroids. The 2-4-h transient post-infusion partial thromboplastin time prolongation values, a class effect of phosphorothioate oligonucleotides, were 18, 21 and 23 s for 250, 300 and 350 mg, respectively.

CONCLUSIONS:

Alicaforsen (ISIS 2302), at fixed doses of 300 and 350 mg, achieved the desired drug exposure and may be an effective therapy for Crohn's disease. Infusion-related reactions were observed less frequently in patients on corticosteroids, and with decreasing frequency with continued treatment.

• Authors: B R Yacyshyn, C Barish, J Goff, D Dalke, M Gaspari, R Yu, J Tami, F A Dorr, K L Sewell
• Journal: Alimentary pharmacology & therapeutics (Aliment Pharmacol Ther) Vol. 16 Issue 10 Pg. 1761-70 (Oct 2002) ISSN: 0269-2813 [Print] England
• PMID: 12269969 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Gastrointestinal Agents
• Glucocorticoids
• Immunosuppressive Agents
• Oligodeoxyribonucleotides, Antisense
• Phosphorothioate Oligonucleotides
• Thionucleotides
• alicaforsen

Topics

• Adolescent
• Adult
• Area Under Curve
• Crohn Disease (blood, drug therapy)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Drug Therapy, Combination
• Female
• Gastrointestinal Agents (adverse effects, blood, therapeutic use)
• Glucocorticoids (administration & dosage)
• Humans
• Immunosuppressive Agents (adverse effects, blood, therapeutic use)
• Male
• Middle Aged
• Oligodeoxyribonucleotides, Antisense (administration & dosage, blood, therapeutic use)
• Phosphorothioate Oligonucleotides
• Remission Induction
• Thionucleotides (administration & dosage, blood, therapeutic use)
• Treatment Outcome