Ustekinumab (USTE, Stelara®; Centocor Ortho Biotech Inc., PA, USA and Janssen Cilag, High Wycombe, UK) is a fully human IgG1k mAb against the p40 subunit of IL-12 and -23, inhibiting the activity of these cytokines.[119,120] IL-12 and -23 are critical for the maintenance of autoreactive effector Th17 cells. USTE was approved as a second-line treatment for moderate-to-severe psoriasis in Europe and Canada in 2009 after having shown high clinical efficacy and a favorable risk–benefit profile in two large controlled clinical trials.[122,123] Much evidence has suggested important roles of IL-12 and -23 in animal models of MS,[124–127] and overexpression of these cytokines was demonstrated in circulating mononuclear cells from MS patients[128,129] and in MS brain lesions.[130,131] These data provided a strong rationale for the investigation of USTE as an immunomodulatory treatment of MS.
A randomized, double-blind, placebo-controlled, multicenter Phase II trial investigated the safety and efficacy of USTE in 249 patients with RRMS. Study participants received subcutaneous injections of placebo or one of four different USTE dosages at weeks 0, 1, 2, 3, 7, 11, 15 and 19. USTE doses were 27, 90 q8w, 90 and 180 mg per injection, with the 90 mg q8w dosage group receiving a placebo substitute at weeks 7 and 15. Baseline data were comparable between the five groups. The cumulative number of new Gd-enhancing MRI lesions on serial cranial scans through week 23 was defined as the primary end point. Patients were followed-up through week 37. Surprisingly, it was found that USTE did not reduce, but rather increased by trend the cumulative number of Gd-enhancing MRI lesions in the USTE groups in comparison with patients receiving placebo. Relapse rate and EDSS progression as secondary end points did not differ between the groups either. However, the median EDSS score did not change in any of the groups, including the placebo group. Adverse effects were reported in 78% of placebo- and 85% of USTE-treated patients. Adverse effects more frequently observed in USTE- than in placebo-treated patients included infections needing treatment (28 vs 16%), injection-site reactions (32 vs 14%), headache (14 vs 4%) and fatigue (13 vs 2%). Two patients in the USTE groups were diagnosed with malignant diseases (tonsil or colon cancer) shortly after treatment initiation, and recovered fully after appropriate treatment. Both cancer cases were probably not related to USTE treatment.
In conclusion, despite a strong rationale, USTE did not prove useful in the treatment of RRMS. The authors of the study speculated that USTE might not have crossed the BBB at sufficient concentrations to antagonize IL-12 and -23 in MS brain lesions, that it might take effect only at the initial stage of the disease or that the Th1/Th17 axis is less important in the pathogenesis of the disease than currently thought. A deeper discussion, favoring the second hypothesis, was recently published in this journal. At present it remains unclear why this clinical trial failed.
Expert Rev Neurother. 2010;10(5):791-809. © 2010 Expert Reviews Ltd.
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