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.

Inclusion criteria

1. Males and females between the ages of 18 and 70 years, inclusive.

2. Diagnosis of clinically definite MS according to the McDonald Criteria.

3. Must have been on conventional immunomodulatory treatment (interferon beta-1a,
glatiramer acetate, or natalizumab) for at least 3 months OR have not tolerated
conventional treatment OR have refused to start conventional treatment.

4. 2 or more total gadolinium enhancing lesions on each of two pretreatment MRI scans at
screening and enrollment.

5. Subject must have EDSS ranging from 1.5 to 6.5.

6. Subject must have had at least one clinical exacerbation in the last year and this
must have occurred after having been on Avonex, Betaseron, Copaxone, Rebif or
Natalizumab therapy for at least 3 months. This does not apply if subject has refused
to start conventional therapy.

7. Subject must have had a sustained (≥ 3 months) increase of > 1.0 on the EDSS
(historical estimate allowed) between 3.0 and 5.5 or > 0.5 between 5.5 and 6.5 (while
on therapy).

8. Written informed consent prior to any testing under this protocol, including screening
tests and evaluations that are not considered part of the subject's routine care.

9. Women of childbearing potential should have a negative pregnancy test prior to entry
into the study.

Exclusion criteria

1. Any risk of pregnancy--ALL female patients must have an effective means of birth
control or be infertile due to hysterectomy, fallopian tube surgery, or premature
menopause.

2. Cardiac ejection fraction of < 45%.

3. Serum creatinine > 2.0.

4. Patients who are pre-terminal or moribund.

5. Bilirubin > 2.0, transaminases > 2x normal.

6. Patients with EDSS < 3.0 or > 6.5.

7. Patients with pacemakers and implants who cannot get serial MRIs.

8. Patients with active infections until infection is resolved.

9. Patients with WBC count < 3000 cells/µl, platelets < 100,000 cells/µl and untransfused
hemoglobin < 10 g/dl.