title: Dose ranging pharmacokinetic trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn's disease.
abstract: OBJECTIVE
  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.affiliation: University of Alberta, Edmonton, AB, Canada. bruce.yacyshyn@med.va.gov
authors.forename: B R
authors.initials: BR
authors.lastname: Yacyshyn
authors.forename: C
authors.initials: C
authors.lastname: Barish
authors.forename: J
authors.initials: J
authors.lastname: Goff
authors.forename: D
authors.initials: D
authors.lastname: Dalke
authors.forename: M
authors.initials: M
authors.lastname: Gaspari
authors.forename: R
authors.initials: R
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Tami
authors.forename: F A
authors.initials: FA
authors.lastname: Dorr
authors.forename: K L
authors.initials: KL
authors.lastname: Sewell
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D003424:Crohn Disease / Q000097:blood* / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D054735:Phosphorothioate Oligonucleotides; D012074:Remission Induction; D013873:Thionucleotides / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D005765:Gastrointestinal Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D020319:Oligodeoxyribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D013873:Thionucleotides; C089753:alicaforsen