1. To evaluate safety and tolerability of 5 mg dose over a nine-month treatment period
2. To compare effect of 5 mg dose vs. placebo on total Gd-enhancing lesion score after nine months of treatment
1. To evaluate effect of 5 mg dose on other cranial MRI scores and on EDSS outcome measure after nine months of treatment
2. To define the effects of NBI-5788 on the immune response and link this with any effect on clinical-MRI responses mechanism of action based on current state-of-the-art immunologic studies.
BASIS/RATIONALE: NBI-5788 has been administered to 205 MS patients at doses of 1, 3, 5, 10, 20, and 50 mg in one Phase 1 and two Phase 2 trials. In the 8-patient open-label Phase 2 study, four patients experienced exacerbations. In two of these cases investigators concluded that the exacerbation could be linked to an APL-induced expansion of T-cells specific for MBP(83-99). No excess of MS relapses with APL treatment was observed in the placebo-controlled trials.
Analyses of the larger Phase 2 study conducted in 142 patients with relapsing-remitting MS treated with placebo, 5, 20 or 50 mg of NBI-5788, suggested treatment benefit for the 5-mg group with respect to several secondary Magnetic Resonance Imaging (MRI) efficacy measures. In addition to adverse events expected for an MS population, there were an excess of injection site reactions and systemic hypersensitivity reactions seen primarily at the higher dose levels (20 and 50 mg). There was a correlation in the severity of the injection site reaction and increasing dose of NBI-5788. Hypersensitivity reactions included dysphagia, vesicles, hives, rash and parasthesia. There were no incidences of anaphylaxis. A statistically significant treatment benefit was seen for the 5-mg dose in comparison to placebo with respect to reduction from baseline to weeks 12 and 16 in the total volume of Gadolinium (Gd)-enhancing lesions. A trend toward statistical significance was also seen for the 5-mg group over placebo with respect to the reduction from baseline to weeks 12 and 16 in the total number of Gd-enhancing lesions. These significance tests were not adjusted for multiplicity of testing, and thus provide only suggestive evidence of treatment benefit. The current study is intended to provide the opportunity to confirm whether it is possible, at the 5 mg dose, to reduce MRI lesion number while avoiding hypersensitivity reactions.
SIGNIFICANCE: Two phase II trials have been done to date with the APL; a small (8 patient) open-label trial and a multi-center, double-blind, placebo controlled study involving approximately 144 patients. The results from these two trials show that the top dose (50 mg) resulted in significant safety issues (e.g. hypersensitivity). This phenomenon is not unexpected to immunologists given the vigor with which the APL was administered (50mg weekly). However, at the low dose (5 mg, weekly) there was evidence of a change in the MRI status (both a reduction in the volume and number of new enhancing lesions). In spite of claims to the contrary, new treatments are needed in addition to the current FDA approved therapies.
RELEVANCE: The proposed study is consistent with the mission of the ITN, to develop and implement clinical strategies and biological assays for the purpose of monitoring tolerance in autoimmune disease. Even with the controversies surrounding the APL approach, fundamental questions regarding the induction and maintenance of Th2-cells and their control of autoimmune phenomenon remain unanswered. Careful, well-controlled experiments are required to answer whether or not the APL has any therapeutic value.
PROTOCOL SUMMARY: This is a multicenter, randomized, double-blind, placebo-controlled trial in which qualifying patients will be randomized 2:1 to receive active drug or placebo. Following a 4-week run-in phase in which patients will have two baseline MRIs, patients will enter a 4 week induction phase, during which they will be receive injections weekly (5 doses ), then a 32-week maintenance phase during which injections are monthly (8 doses). A final follow-up visit will be conducted 4 weeks after the last injection. Eligible patients must have MS with relapse, have had one or more relapses during the prior 2 years, 1-10 gadolinium (Gd)-enhancing lesions on the Run-in MRI, and an EDSS of 6.5 or less. There are exclusions for certain prior MS treatments and medical / psychiatric conditions. The primary efficacy parameter is a summary change score of the mean number of total Gd-enhancing lesions at weeks 36 and 40 minus the mean number for the two baseline scans. Safety monitoring will include AE/SAE reporting, physical exams, vital signs, ECG. CXR, laboratory tests, neurologic evaluations, and systemic hypersensitivity and injection site assessments. All study medications will be administered by study personnel and patients will remain under observation for a minimum of 2 hours post-injection. An independent Data Safety and Monitoring Board will oversee the safety of the trial.