Mark K. Wedel

BACKGROUND: Apolipoprotein B (apoB) is an important structural component of low-density lipoprotein cholesterol (LDL-C) and plays a key role in LDL-C transport and removal. Reduction in apoB synthesis is expected to reduce circulating LDL-C, a proven risk factor of cardiovascular disease. In the present study, we describe the outcome of the first-in-humans study on the safety and efficacy of an antisense oligonucleotide inhibitor of apoB. METHODS AND RESULTS: This study was a double-blind, randomized, placebo-controlled, dose-escalation investigation conducted at a single site in 36 volunteers with mild dyslipidemia. The study utilized an initial single dose of 50 to 400 mg of ISIS 301012, a 20-mer oligonucleotide, followed by a 4-week multiple-dosing regimen with the same assigned dose. Safety was assessed by the incidence, severity, and relationship of adverse events to dose. Efficacy was determined by changes in serum apoB and LDL-C relative to baseline and placebo. The most common adverse event was erythema at the injection site (21 of 29 subjects). ApoB was reduced by a maximum of 50% (P=0.002) from baseline in the 200-mg cohort. This decrease in apoB coincided with a maximum 35% reduction of LDL-C (P=0.001). LDL-C and apoB remained significantly below baseline (P<0.05) up to 3 months after the last dose. CONCLUSIONS: Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apoB and LDL-C. Although injection-site reactions were common, adherence to protocol was unaffected.

RATIONALE: Despite recent clinical trials demonstrating improved outcome in acute respiratory distress syndrome (ARDS), mortality remains high. Partial liquid ventilation (PLV) using perfluorocarbons has been shown to improve oxygenation and decrease lung injury in various animal models. OBJECTIVE: To determine if PLV would have an impact on outcome in patients with ARDS. METHODS: Patients with ARDS were randomized to (1) conventional mechanical ventilation (CMV; n=107), (2) "low-dose" perfluorocarbon (10 ml/kg; n=99), and (3) "high-dose" perfluorocarbon (20 ml/kg; n=105). Patients in all three groups were ventilated using volume ventilation, Vt <or= 10 ml/kg predicted body weight, rate <or= 25/min, inspiratory-to-expiratory ratio <or= 1:1, Fi(O(2)) >or= 0.5, and positive end-expiratory pressure >or= 13 cm H(2)O. RESULTS: The 28-d mortality in the CMV group was 15%, versus 26.3% in the low-dose (p=0.06) and 19.1% in the high-dose (p=0.39) PLV groups. There were more ventilator-free days in the CMV group (13.0+/-9.3) compared with both the low-dose (7.4+/-8.5; p<0.001) and high-dose (9.9+/-9.1; p=0.043) groups. There were more pneumothoraces, hypoxic episodes, and hypotensive episodes in the PLV patients. CONCLUSIONS: PLV at both high and low doses did not improve outcome in ARDS compared with CMV and cannot be recommended for patients with ARDS.

BACKGROUND: Pouchitis is the major long-term complication of ileal pouch-anal anastomosis for ulcerative colitis. The incidence of pouchitis is as high as 50% several years after surgery. Two-thirds of pouchitis patients suffer recurrence. Of those who recur, one-quarter suffer from chronic, unremitting pouchitis. Current treatments for this disorder are disappointing. AIM: To determine whether a topically administered enema formulation of ISIS 2302 (alicaforsen), an antisense inhibitor of intercellular adhesion molecule-1, can improve the clinical symptoms, endoscopic mucosal appearance and mucosal histology in patients with chronic, unremitting pouchitis, a disorder in which this molecule is over-expressed. METHODS: In an open-label, uncontrolled study, 12 patients with chronic, unremitting pouchitis were treated with 240 mg alicaforsen antisense enema nightly for 6 weeks. Clinical evaluation and endoscopy were performed at baseline and at weeks 3, 6 and 10. Pouchoscopy with biopsy was carried out at baseline and at weeks 6 and 10. The primary end-point was the reduction from baseline of the Pouchitis Disease Activity Index (PDAI) at week 6. Secondary end-points included the PDAI at week 10. Safety was evaluated by analysing the adverse events, vital signs and laboratory parameters. RESULTS: After 6 weeks of nightly alicaforsen enema, a statistically significant (n = 12, P = 0.001) reduction in the PDAI from baseline (11.42) to week 6 (6.83) was observed. Mean reductions in the endoscopy sub-score from baseline (5.25) to week 3 (3.08) and week 6 (2.58) were statistically significant (P = 0.0039 and P = 0.0005, respectively). The mean reductions in clinical symptom sub-score from baseline (3.75) to week 3 (2.33) and week 6 (2.25) were also statistically significant (P = 0.0156 and P = 0.0117, respectively). Ten of the 12 patients achieved a mucosal appearance score of 0 or 1 at endoscopy. Five of the 12 patients (42%) had a non-statistically significant decrease in the histology component of their PDAI from baseline to week 6. By week 6, seven of the 12 patients (58%) were in remission, as defined by PDAI < 7, with a mean decrease from baseline in PDAI score of six points. The alicaforsen enemas were well tolerated and no serious side-effects were noted. CONCLUSIONS: Antisense enema to intercellular adhesion molecule-1 is safe and well tolerated. In an open-label trial, it appeared to improve the PDAI score, clinical symptoms and endoscopic mucosal appearance. It may also improve the histology. In the light of the responses observed in this trial, a randomized, placebo-controlled trial is warranted.

BACKGROUND: Alicaforsen is an antisense oligonucleotide designed to inhibit expression of human intercellular adhesion molecule 1. Previous clinical studies have demonstrated activity of alicaforsen enema in ulcerative colitis and pouchitis. AIM: To determine the minimally effective dosing regimen of alicaforsen enema in subjects with mild to moderate left-sided ulcerative colitis. METHODS: Randomized, placebo-controlled, double-blind, two-dose ranging multicentre study. One hundred and twelve subjects were equally randomized to receive one of four alicaforsen enema regimens or placebo daily for 6 weeks. Primary end point was Disease Activity Index at week 6. Secondary end points included evaluation of clinical improvement, relapse rates and durability of response. Analysis of data were performed on the intent-to-treat population. RESULTS: No significant difference was observed between treatment arms and placebo in the primary end point. A prolonged reduction in mean% Disease Activity Index relative to baseline was observed in the daily 240 mg alicaforsen enema treatment arm in comparison with placebo from week 18 (51% vs. 18%, P=0.04) to week 30 (50% vs. 11%, P=0.03). CONCLUSIONS: Alicaforsen enema was safe and well tolerated at all doses studied. The durability of the response to alicaforsen enema treatment may suggests a disease-modifying effect.