Humanized Anti-tac  and Raptiva therapy In The Treatment Of Uveitis

Nussenblatt, Robert

Abstract

We have engaged in a series of studies to evaluate the long term safety and potential therapeutic activity of humanized anti-IL-2 receptor monoclonal antibody (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior non-infectious uveitis. This was based on our initial observations in an animal model for human uveitis. Our initial study in patients was a non-randomized, open-label study to evaluate the long term safety and potential therapeutic activity of daclizumab. In that study, patients with chronic, non-infectious bilateral, sight-threatening uveitiswere weaned off their immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Anti-Interleukin 2 receptor antibody therapy appeared to prevent the expression of severe sight-threatening intraocular inflammatory disease in most patients, based on the primary end point of a loss of vision of 10 letters or more from baseline in either eye. All patients were able to tolerate the study medications without the need for dose reduction. Some patients at one year of therapy were randomized to therapy intervals of 6 weeks, with most of those receiving therapy at 6 week intervals having recurrences of their disease. 7/10 Patients have now received anti-IL2 receptor therapy for up to 4 years. No apparent increase in the infection rate has been seen in these patients. Those patients were converted to monthly subcutaneous administration of the medication instead of infusions. Patients have tolerated this transition with no problems. Based on these findings we have initiated a second study. : Fifteen study participants with sight-threatening uveitis quiescent on immunosuppressive therapy were enrolled at 3 sites and treated with subcutaneous daclizumab, 2 mg/kg every 2 weeks x2, then maintenance at 1 mg/kg every 2 weeks, with simultaneous tapering of the standard immunosuppressive therapy. Treatments were well tolerated and 11/15 patients reached the preset outcome by eliminating 50% of their standard immunosuppressive medications by 12 weeks without recurrence of their ocular inflammatory disease or reduction in visual acuity. Of the 10 participants that have completed 6 months of followup, 9 were able to reduce or maintain 50% of their baseline medication load without significant loss of vision or increase in disease activity. A randomized masked trial using Daclizumab in the treatment of Behcet's disease was completed and the mansucript has been submitted for review. A study was performed in a small number of patients who had active uveitis in spite of standard immunosuppressive therapy. All the patients'disease responded to the administration of high dose (8mg/kg followed by 4mg/kg) therapy with good results. A pilot study using the high dose regimen of daclizumab in the treatment of juvenile rheumatoid arthritis has been completed with the initial findings suggesting that this approach may have beneficial clinical effects. Discussions continue at developing a Phase III study. Efalizumab (Raptiva), a humanized anti-CD11a monoclonal antibody shown to reversibly inhibit leukocyte adhesion and trafficking. We evaluated the safety and efficacy of treating macular edema, secondary to non-infectious intermediate and posterior uveitis, with open label efalizumab in a nonrandomized, prospective study. A total of 6 participants with intermediate and/or posterior/panuveitis with CME was enrolled in the study between October 2006 and January 2009. The average age of participants was 42, 3 participants were female and 3 were male. All patients showed a reduction in CME which was the primary outcome of the study, and improvement in vision. The study database closed as of January 7, 2009. Three IND safety reports have been submitted regarding 1 participant who became pregnant and 2 participants whose partners became pregnant while receiving study medication. No serious adverse events attributable to the study medication were reported by the patients and they tolerated the medication well. Publication of the results of this trial are pending.