Glatiramer Acetate for Multiple Sclerosis With Autoimmune Comorbidities

Multiple Sclerosis (MS) is an auto-immune neurodegenerative disease that affects more than
400,000 individuals in the United States, and 2.5 million worldwide
(www.nationalmssociety.org). The main pathogenic mechanism in MS involves an inflammatory
condition that damages the myelin of the central nervous system (CNS), resulting in axonal
damage and neurological impairment, often leading to severe disability. MS is one of the
most common causes of neurological disability in young and middle-aged adult individuals,
and as such has a tremendous physical, psychological and social impact on patients' lives.
MS is a complex disease diagnosed by McDonald criteria with different clinical and
pathological phenotypes. Several forms of MS have been described: Relapsing-Remitting
(RRMS), Secondary-Progressive MS (SPMS), Progressive-Relapsing MS (PRMS), and
Primary-Progressive MS (PPMS).

Glatiramer Acetate (GA) and Beta-Interferons (β-IFNs) are well established first-line
immunomodulating treatment options for relapsing remitting multiple sclerosis (RRMS) with
excellent safety profiles. The mechanisms of action of GA and IFNs are different. It is well
known that in general Disease-Modifying Treatments (DMTs) reduce relapse rate in more than
half of the multiple sclerosis (MS) patients who receive DMT, while having little if any
effect on the rest. It has been speculated that the response to beta-interferons or GA may
have genetic basis. As Axtell RC et al. indicated the experimental autoimmune
encephalomyeilits (EAE) in mouse caused by TH1 cells generally respond well to
interferon-beta, while EAE caused by TH17 cells get worse with interferon-beta.

Autoimmune disease is an extreme situation where the autoimmune response overshoots and goes
out of control. The other extreme is a degenerative disorder, where the autoimmune response
is not strong enough for effective protection, and degeneration therefore continues. GA
being an immunomodulator may provide both properly regulated immune suppression (in the case
of autoimmune disease) and properly regulated immune activation (in the case of the
neurodegenerative disease).

Autoimmune conditions cluster in families with high risk for multiple sclerosis than in
general population which suggests that the disease might arise on a background of a
generalized susceptibility to autoimmunity. Occurrence of psoriasis, autoimmune thyroiditis,
vasculitis, rheumatoid arthritis, scleroderma, lupus are seen more commonly in MS patients.
Many of these patients initially get started on beta-IFNs, and usually do not do well on
them. According to Investigator's and the USC MS Comprehensive Care Center experience,
autoimmune co-morbidity associated with MS can serve as a biological marker predicting good
response to GA and unfavorable response to the IFNs.

Inclusion Criteria:

- Clinically definite multiple sclerosis defined by McDonald Criteria.

- Between 18-60 years of age.

- Subject must able to understand and sign the IRB- approved informed consent form
prior to the performance of any study-specific procedures and is willing to comply
with the required scheduling and assessments of the protocol.

- Subjects who are women of childbearing potential, must have a negative serum
pregnancy test at the screening visit, and must be willing to practice a reliable
birth-control method.

- Subjects must have officially diagnosed and documented co-morbid, other than MS,
autoimmune condition (psoriasis, vasculitis, thyroiditis or rheumatoid arthritis).

- At the time of enrollment patients were on beta IFN (Avonex, Betaseron or Rebif)
treatment for at least 3 months.

Exclusion Criteria:

- Women who are either pregnant or breastfeeding, and women of child-bearing potential
(defined as not surgically sterile or at least two years postmenopausal) who are not
using one of the following birth control methods: tubal ligation, implantable
contraception device, oral, patch, injectable or transdermal contraceptive, barrier
method or sexual activity restricted to vasectomized partner.

- Any clinically significant general health conditions that may interfere with the
trial participation.

- Subject has a history of drug or alcohol abuse within the past year.

- Subject had corticosteroid treatment within last 90 days.

- Subject started new medication within last 30 days.

- Subject is a participant in another research project.

- Subject has contraindications for GA treatment.