Matthew Frankel

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany

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Publications (5)53.29 Total impact

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    ABSTRACT: Pilot studies with visilizumab, a humanised monoclonal antibody to CD3, suggest efficacy for corticosteroid-refractory ulcerative colitis (UC). A placebo-controlled trial was warranted. A randomised, double-blind, placebo-controlled study evaluated the efficacy of visilizumab induction treatment in 127 patients with severely active UC despite treatment with ≥5 days of intravenous corticosteroids. Patients received placebo or visilizumab 5μg/kg intravenously on days 1 and 2. Corticosteroids were tapered according to disease activity. Patients were followed up for 90 days. The primary end point was induction of response at day 45. Secondary end points included remission and mucosal healing at day 45, symptomatic response at day 15 and colectomy. Response at day 45 occurred in 55% of patients receiving visilizumab compared with 47% of those who received placebo (p=0.475). Remission at day 45 occurred in 8% of patients receiving visilizumab compared with 9% of those who received placebo (p=0.704). Mucosal healing at day 45 occurred in 29% of patients receiving visilizumab compared with 26% of those who received placebo (p=0.799). Symptomatic response at day 15 occurred in 82% of patients receiving visilizumab compared with 74% of those who received placebo (p=0.244). Colectomy was performed in 18% of patients receiving visilizumab compared with 7% of those who received placebo (p=0.130). Cardiac disorders and vascular disorders occurred more frequently in the patients who received visilizumab. Visilizumab at a dose of 5μg/kg for two consecutive days was not effective for severe, corticosteroid-refractory UC and was associated with increased cardiac and vascular adverse events. (Registered at http://www.clinicaltrials.govNCT00279422/).
    Gut 11/2010; 59(11):1485-92. · 13.32 Impact Factor
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    ABSTRACT: Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). In all, 104 patients were treated. In Stage I, 73 patients were randomly assigned to receive intravenous visilizumab 5, 7.5, 10, or 12.5 microg/kg/day for 2 consecutive days. In Stage II, 33 patients received visilizumab at the optimal clinical dose (OCD) of 5 microg/kg/day for 2 days. Symptomatic response and remission were defined by the modified Truelove-Witts severity index. Clinical response and remission were defined by the Mayo score. The rates of symptomatic response at day 15 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 70%, 50%, and 61%, respectively, in Stage I and in 54% in Stage II. The symptomatic remission rates were 35%, 5%, 22%, and 11% in Stage I and 18% in Stage II. The rates of clinical response at day 30 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 65%, 50%, and 67%, respectively, in Stage I and 55% in Stage II. The clinical remission rates were 6%, 5%, 0%, and 11% in Stage I and 6% in Stage II. All patients experienced adverse events. Serious adverse events included abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster, and esophageal candidiasis. Treatment with visilizumab induced symptomatic response and clinical response. Results with 5 microg/kg/day were similar to those observed with higher doses.
    Inflammatory Bowel Diseases 09/2009; 16(4):620-9. · 5.12 Impact Factor
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    ABSTRACT: Monoclonal antibodies to CD3 and CD4 T-cell receptors are evolving for Crohn's disease (CD) and ulcerative colitis. Their administration is often associated with a cytokine release syndrome (CRS). We evaluated data from two prospective clinical trials (NCT00267709 and NCT00267722) of visilizumab (HuM291), a novel humanized anti-CD3 antibody, in 34 patients with CD who received 10 microg/kg intravenously on 2 consecutive days. Serum hepatic tests including bilirubin, alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), visilizumab concentrations, and a panel of 16 cytokines were measured pre- and postadministration of visilizumab. Patients experienced CRS symptoms at a median of 45 min postinfusion. The cytokine profile was characterized by interferon-inducible protein-10 (IP-10), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, monocyte chemotactic protein 1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-2 (IL-2), and interleukin 1 receptor antagonist (IL-1Ra), which were elevated between 6 (IL-1Ra) and 870 (IP-10) times their baseline concentrations. TNF-alpha and IL-2 peaked at the first day 1 h post infusion, whereas all others peaked at 6 h post infusion. Eighty-six percent of patients experienced an elevation above the upper limit of normal in hepatic enzymes (GGT 73%, AST 73%, ALT 64%, and AP 42% of patients), but not bilirubin, within 6 h postinfusion. Transient elevation of hepatic enzymes occurred frequently in patients with CD treated with visilizumab and was associated with CRS. CD patients could be predisposed due to an aberrant expression of adhesion molecules in the liver that promotes CRS upon engagement of the T-cell receptor and may relate to extraintestinal disease manifestations such as primary sclerosing cholangitis.
    The American Journal of Gastroenterology 03/2009; 104(4):868-76. · 9.21 Impact Factor
  • Gastroenterology 01/2009; 136(5). · 12.82 Impact Factor
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    ABSTRACT: 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. In this open-label phase 1 study, 32 subjects received visilizumab at a dose of 10 or 15 microg/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. Eight patients received 15 microg/kg visilizumab. Because of dose-limiting toxicities (T-cell recovery >30 days in 2 of 8 patients), the dose was reduced to 10 microg/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-microg/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. Visilizumab had an acceptable safety profile at the 10-microg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid-refractory ulcerative colitis.
    Gastroenterology 11/2007; 133(5):1414-22. · 12.82 Impact Factor