The Center Without Walls has several collaborative studies under way in various stages of development:
Oral Interferon Tau
Twenty eight patients with relapsing remitting MS or clinically isolated syndromes suggestive of early MS have participated in this study at 4 of the Centers (Harvard, OHSU, USC and UCSF). Oral interferon tau taken during 9 months has been well tolerated. Jeff Cohen at the Cleveland Clinic served on the Data and Safety Monitoring Board. Preliminary analysis suggests that oral interferon tau decreases MS activity on serial brain MRI scans by approximately 60%. Final analysis will be provided for the third quarter of 2007. A randomized phase II study is expected to start within the next few months. Oral interferon may turn out to be comparable to approved interferon beta with fewer side effects, and it is easier to administer. No support is requested.
Treatment decreases B cells and antibodies against the nervous system
All seven Centers have been involved in a new treatment strategy using rituximab, a monoclonal antibody against the B cell marker CD20 that depletes B cells for over 6 months after the first course of treatment. B cells are believed to participate to MS brain inflammation and make antibodies against constituents of the brain. The results of the randomized, placebo controlled phase II trial establishes for the first time the role of B cells as key players during MS inflammation in 104 patients with relapsing remitting MS (Protocol Chairs: Drs Stephen Hauser and Emmanuelle Waubant, UCSF). Depleting B cells with one course of rituximab decreases disease activity on serial brain MRI scans by 90% and lessens relapses by over 50% compared to placebo. These exciting results were presented at the American Academy of Neurology in Boston in May by Dr Hauser. Rituximab is administered intravenously every six months. It is FDA approved for non-Hodgkin lymphoma and rheumatoid arthritis, and is well tolerated except for mild to moderate infusion-related reactions. The small phase I study of re-treatment with rituximab confirms safety in 26 patients, and shows that the benefit of rituximab is maintained until the end of the first year of therapy upon re-treatment. These very encouraging results will be confirmed in a large phase III trial expected to start in 2008 that will hopefully lead to FDA-approval of this drug for patients who have relapsing forms of MS.
Add-on therapy for patients doing poorly on interferon therapy
This study, headed by the Cleveland MS center and sponsored by Biogen Idec, is the first large pivotal study of combination therapy. Dr. Calabresi at Johns Hopkins participated to the Data and Safety Monitoring Board for this study. Six of the Centers (Cleveland, UCSF, USC, Yale, Johns Hopkins and OHSU) have participated in this trial that compared the benefits of adding monthly Solumedrol or oral methotrexate to Avonex in patients who experienced exacerbations while on Avonex. The results of this study were presented at the American Academy of Neurology in Boston in May by Dr Cohen from the Cleveland Clinic. The study shows that patients who received IV Solumedrol pulses in addition to Avonex, or Avonex and methotrexate tended to develop less new lesions on the follow-up brain MRI scan at 1 year compared to patients who received Avonex only, or Avonex and methotrexate. This has direct implications for the treatment of patients who respond incompletely to Avonex as physicians may now stop adding oral methotrexate to Avonex, and will instead prefer to combine Avonex to IV Solumedrol pulses.
The Nancy Davis Center Without Walls (CWW) program has become a leading consortium in the development of promising agents for multiple sclerosis (MS). The strategy of the CWOW is first to evaluate novel treatment approaches in single-center or two-center studies which, if proven promising, are later developed collectively.
The NDCWW has continued or initiated patient enrollment in several collaborative clinical trials of oral medications for MS that have been designed by the NDCWW. The Center has also continued the collaborative study of a novel intravenous drug, rituximab, in primary progressive MS.
Lipitor (atorvastin) for patients with early multiple sclerosis
Seventy four patients have been enrolled nationwide in this study. We are planning to enroll 152 patients with their very first MS event and monitor for one year the effect of Lipitor compared to placebo. With this study, 6 of the Centers (UCSF, Cleveland, USC, Yale, OHSU and Johns Hopkins) are following up on the exciting work in animal models suggesting that Lipitor significantly decreases the activation of the immune system that occurs in MS. Since Lipitor may also have neuroprotective properties, the centers use spectroscopy, a sophisticated magnetic resonance technique, to determine whether Lipitor prevents brain damage. This is an exciting trial, as the medication is given orally and is much safer than many immunologic therapies considered for MS. This is also one of the first times the CWW centers are able to share their advanced magnetic resonance technology. The study designed by UCSF is sponsored by the Immune Tolerance Network, Biogen Idec and Pfizer.
Memantine for MS cognitive impairment
This year OHSU, in collaboration with USC, has conducted a double blind placebo-controlled pilot trial of memantine for cognitive impairment in MS. Memantine is a glutamate receptor antagonist that has been shown to improve cognition in Alzheimer’s disease. This trial is designed to assess whether memantine will improve cognition among MS patients. Eighty patients have already been enrolled in the study.
Treatment that decreases B cells and antibodies against the nervous system
The large double blind trial that will evaluate the efficacy of rituximab in patients with primary progressive MS over two years (Protocol Chairs: Kathleen Hawker, Cincinnati and Jack Antel, Montreal) is almost completed. Over 400 patients are participating. We anticipate the results to be available by early 2008. If this study is positive, rituximab could become the first therapy for primary progressive MS. Genentech, the study sponsor, has agreed to support state-of-the-art immunological studies that will help understand the role of B cells in MS and the effect of the medication.
Recombinant T Cell Ligand Therapy
Two of the Centers, OHSU and Yale, have initiated a Phase I safety and dose finding study of the DR2-MOG 35–55 RTL, referred to as RTL1000. Patients with MS and positive for a specific marker (DR2+) will receive single i.v. infusions of RTL1000 of increasing doses (6–300 mg). The first patient has been enrolled. Outcomes will be safety, including MRI monitoring for disease activation and antibody formation to the RTL1000. This is the first step in developing RTL1000 as a novel immunotherapy for MS.
Harvard is planning a multicenter phase II trial with CTL4-Ig based on the data reported last year for the phase I trial done at their center. CTLA-4Ig blocks T cell activation and suppresses inflammation. The data from the pilot study showed that CTLA-4Ig is safe in MS and there is evidence of biologic activity by changes in the immune markers in the blood.
Sodium channel expression within human MS lesions
Yale and Cleveland are examining the slow burn of axons in chronic lesions which have been implicated to play a major role in MS disability.