Modes of Action
Propagation of a population of protective natural killer cells, characterized by high expression of CD56, was suggested as a mode of action of the anti-CD25 mAb daclizumab (DAC) in MS patients, a result that was recently confirmed in the CHOICE cohort. Therefore, this cell population might serve as an efficacy biomarker. A recent study prospectively investigated the effect of DAC on CD4+CD25+Foxp3+ Tregs in 15 patients with RRMS. Tregs are supposed to play a protective role in a number of T-cell-mediated autoimmune disorders, and impaired Treg function has been described in some cohorts of MS patients.[115,116] A reduction of Treg frequency and function by DAC was observed in this study. Nevertheless MRI disease activity was reduced in the overall cohort, and Treg frequency did not negatively correlate with MRI disease activity. However, dermatitis was observed in three out of 15 individuals, possibly indicating an undesired effect of reduced immune tolerance in a non-CNS immune compartment. The authors concluded that Treg reduction in the peripheral blood did not negatively affect immune tolerance within the CNS – possibly due to parallel DAC effects on other immune cell subpopulations. The modes of DAC action in MS patients remain to be further elucidated.
New Open-label Clinical Data in MS Patients
A single center Phase II study in 15 patients with RRMS (n = 12) or secondary progressive MS (n = 3), and clinical plus MRI evidence for disease activity despite treatment with an IFN-β preparation, investigated DAC as an add-on treatment for 5.5 months and then as a monotherapy for further 10 months, if patients showed a MRI response to the combination therapy. Treatment had to be stopped in two patients with relapsing–remitting disease owing to systemic immune responses a few weeks after IFN-β withdrawal, characterized by mouth ulcers, photosensitivity rash and transient formation of autoantibodies requiring corticosteroid therapy. One of these patients developed delayed viral myositis 3 months after DAC withdrawal. Nine of the remaining 13 patients experienced stabilization of MRI disease activity under DAC monotherapy, while four patients required additional IFN-β treatment for disease stabilization. These data suggested that most RRMS patients respond well to DAC monotherapy, but that disease stabilization may require a combination with IFN-β in some patients, and that autoimmune adverse effects might be induced by DAC.
Ali and colleagues retrospectively analyzed safety and tolerability of DAC in 55 patients with RRMS (n = 40) or secondary progressive MS (n = 15) who had received intravenous infusions of 1 mg/kg DAC per month and for whom a minimum follow-up of 6 months was available. DAC was used as a monotherapy in 49 patients and as a combination therapy in six patients. Four of these six patients received monthly corticosteroid treatment. DAC therapy was discontinued in 16 out of 55 patients. Reasons included perceived lack of efficacy in ten patients, adverse effects in five patients and financial reasons in one patient. Adverse effects causing treatment termination included hypersensitivity, viral meningitis, infusion reaction, psoriasis in a patient with positive family history and cardiac toxicity. In total, 36 patients reported adverse effects, including fatigue (n = 8), gastrointestinal symptoms (n = 4), rash (n = 3), generalized weakness (n = 3) and cardiotoxicity (n = 2).
Daclizumab High-yield Process Phase III Program in RRMS
Based on an unpublished interim analysis of 150 patients in the placebo-controlled Phase II SELECT monotherapy trial in patients with RRMS, the study target population of originally 297 patients was expanded to 600 patients in July 2009. The estimated final data collection date for the primary outcome measure, which is the annualized relapse rate after 1 year, is September 2011. A Phase III active comparator monotherapy trial in RRMS patients was announced to be starting in March 2010 (NCT01064401). This trial, which was designed to test the superiority of DAC 150 mg subcutaneously once every 4 weeks for 96–144 weeks over once weekly IFN-β1a 30 µg intramuscularly, plans to enroll 1500 patients with confirmed RRMS and a baseline EDSS between 0 and 5.0. In contrast to pretreatment with DAC, pretreatment with an IFN-β formulation is not mentioned as an exclusion criterion on the FDA website, which will complicate the interpretation of the trial results. Relapse prevention was defined as the primary end point. Disability progression and quality of life were defined as key secondary outcome measures. The trial will be conducted in North and South America, Europe, the Russian Federation and Australia, and the planned study completion date is January 2014.
Expert Rev Neurother. 2010;10(5):791-809. © 2010 Expert Reviews Ltd.
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