Trial Information

Phase II Study of High Dose Cyclophosphamide Followed by Glatiramer Acetate in the Treatment of Relapsing Remitting Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by progressive
immune-mediated destruction of myelin and axons within the CNS. Despite the development,
approval and clinical utilization of several medicines for patients with MS, most patients
continue to accrue progressive disability. High-dose cyclophosphamide is chemotherapy
treatment option for severe, refractory, immune-mediated illnesses such as MS. There is
growing evidence that high dose cyclophosphamide is well tolerated and effective in MS. Our
experience with 9 patients who underwent treatment at the Johns Hopkins Hospital yielded
impressive results with a significant 40% reduction in baseline disability and an 81%
reduction in MRI gadolinium enhancing lesions. Five out of 9 patients had recurrence of new
brain MRI lesions during 24 months of follow-up, recurring in 4 patients during the first
year of follow-up. Our findings suggest that high-dose cyclophosphamide holds promise in
inducing remission and reducing disability in relapsing remitting MS however the recurrence
of MS disease activity (evidenced by worsening disability, clinical exacerbations or ongoing
MRI evidence of new lesions) suggests that high-dose cyclophosphamide given as a treatment
on its own, is not sufficient to induce long-term remission.

Glatiramer acetate has been shown to be a more general suppressor of autoimmune disease,
inhibiting the onset of experimental animal models of uveoretinitis, rheumatoid arthritis,
immune rejection of grafts against host and host against graft disease, and inflammatory
bowel disease. Glatiramer acetate was originally developed based on the observation that it
inhibited the onset of clinical disease in an animal model of multiple sclerosis,
experimental autoimmune encephalomyelitis (EAE). Glatiramer acetate suppression of EAE was
found to be a general phenomenon not restricted to a particular species, disease type or
encephalitogen used for the induction of EAE. A unique feature of glatiramer acetate is its
promiscuous binding with high affinity to various class II MHC molecules and it potent
induction of Th2 regulatory T cells. Moreover glatiramer acetate has subsequently been shown
to be a more general suppressor of autoimmune disease, inhibiting the onset of experimental
uveoretinitis, immune rejection of grafts against host and host against graft disease, and
experimental inflammatory bowel disease.

We plan to investigate the properties of glatiramer acetate against the recurrence of MS
disease activity following high dose cyclophosphamide induced cessation detectable
autoimmunity. This study is a prospective, open-label two-year follow-up study in 12
patients with relapsing-remitting MS who are unable to tolerate or have failed to optimally
respond to conventional therapy and are at high risk of disease progression and loss of
function. Patients who elect to enter the study will be given a single course of high-dose,
cyclophosphamide regimen without transplantation. Patients will then receive 20 mg of
glatiramer acetate subcutaneously 4 to 6 weeks after the last dose of high-dose
cyclophosphamide, to allow the immune system to have time to begin to reconstitute without
glatiramer acetate but still provide sufficient time for glatiramer acetate to vaccinate
against recurrence of MS disease activity.

The primary outcome of this pilot study will be to determine if high followed by a
maintenance dose of glatiramer acetate is safe in this patient population. We hypothesize
that institution of glatiramer acetate treatment following high-dose cyclophosphamide
treatment will extend the period of disease free activity and further reduce the disability
in patients with relapsing remitting MS.