Gastroenterology

Gastroenterology

Volume 133, Issue 5, November 2007, Pages 1414-1422
Gastroenterology

Clinical–Alimentary Tract
A Phase I Study of Visilizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Severe Steroid-Refractory Ulcerative Colitis

https://doi.org/10.1053/j.gastro.2007.08.035Get rights and content

Background & Aims: To evaluate the safety and biological activity of visilizumab (a humanized anti-CD3 monoclonal antibody) and to determine a maximum tolerated dose in patients with severe ulcerative colitis that had not responded to 5 days of treatment with intravenous corticosteroids. Methods: In this open-label phase 1 study, 32 subjects received visilizumab at a dose of 10 or 15 μg/kg, administered intravenously on 2 consecutive days. Clinical response was defined as a Modified Truelove and Witts Severity Index <10 with a minimum decrease of 3 points; remission was <4 points. Endoscopic remission was a Mayo endoscopic subscore of 0 or 1. Results: Eight patients received 15 μg/kg visilizumab. Because of dose-limiting toxicities (T-cell recovery >30 days in 2 of 8 patients), the dose was reduced to 10 μg/kg in 24 patients. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission. Forty-five percent of patients did not require salvage therapies or colectomy during the first year postdose. Mild to moderate symptoms of cytokine release occurred in 100% and 83% of patients in the 15- and 10-μg/kg dose groups, respectively. All patients exhibited a rapid decrease in circulating CD4+ T-cell counts, which returned to baseline values by day 30 in 26 of 30 evaluable patients (86%). There were no serious infections. Conclusions: Visilizumab had an acceptable safety profile at the 10-μg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid–refractory ulcerative colitis.

Section snippets

Patients

Male and nonpregnant female patients, 18–70 years of age, who were diagnosed with UC verified by colonoscopy or barium enema within 36 months before study entry and who had active disease were eligible for the study. Active disease was documented by a Modified Truelove and Witts Severity Index (MTWSI) score of 11–21 and ongoing treatment with IV corticosteroids for at least 5 days before study entry.4, 13 Each patient provided written informed consent to participate in the trial before

Patient Screening and Demographics

Of 58 patients who were screened for enrollment, 32 were enrolled and received study drug. Hospitalized patients received IV corticosteroids for a median of 7 days (range, 5–17) before receiving visilizumab. Twenty-five potential patients who were hospitalized with severe UC and treated with IV corticosteroids had measurable EBV DNA levels in whole blood (median, 747 copies/mL; range, 97–10,500 copies/mL) at screening. Six patients with measurable whole blood EBV DNA levels were enrolled in the

Discussion

In a phase 1 dose-finding study, visilizumab had an acceptable safety profile and demonstrated clinical activity in hospitalized patients with IV corticosteroid–refractory UC. There were no serious infectious complications during the study. In this preliminary open-label analysis, visilizumab appeared to produce durable clinical responses that exceeded its pharmacokinetic and pharmacodynamic properties (ie, elimination half-life of 17 hours and transient peripheral blood T-cell lymphopenia

References (20)

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Supported by the sponsor, PDL BioPharma, Fremont, CA.

The authors declare the following conflicts of interest: consultant, PDL BioPharma (S.P., G.V., M.R., D.H., W.S., S.H., S.T., L.M., U.M.); research support for clinical trial, PDL BioPharma (S.P., B.S., G.V., M.R., D.H., W.S., S.H., S.T., L.M., U.M.); speaker at continuing medical education symposia sponsored by PDL BioPharma (S.P., W.S., S.H., D.H.).

ClinicalTrials.gov identifier: NCT00032305.

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