Open-label Study of Liothyronine in MS

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system
(CNS) that is characterized by inflammation, demyelination, and neurodegeneration. It remains
the most common non-traumatic cause of neurologic disability in young adults and presents in
most patients as relapsing-remitting disease. Relapses, caused by inflammatory demyelination,
can result in a significant amount of neurological disability and reduced health-related
quality of life, and having frequent early relapses is associated with increased risk of
longer-term disability. Clinical recovery from early relapses is incomplete in approximately
half of patients with MS. The mechanisms underlying relapse recovery are not completely
understood.

Remyelination of acutely denuded axons is one mechanism by which relapse recovery may occur.
Remyelination is suspected to occur via newly differentiated oligodendrocytes, which are
derived from oligodendrocyte precursor cells (OPCs) in the CNS. However, despite the presence
of this innate repair mechanism, many patients go on to develop progressive functional
disability. This may be due to a failure of remyelination or because of progressive axonal
injury. Chronic demyelinating lesions are surrounded by OPCs and premyelinating
oligodendrocytes, which suggest that failed remyelination does occur and could be partially
due to incomplete oligodendrocyte differentiation. Additionally, recent studies have
highlighted the importance of mitochondrial dysfunction, perhaps related to oxidative stress
or increased energy demands, in mediating MS disease progression. Mitochondrial dysfunction
may drive axonal degeneration with resultant neurodegeneration and progressive neurological
decline (progressive MS). While numerous immune modulating therapies exist, currently, there
is an urgent need for novel therapies that have neuroreparative and neuroprotective
properties.

Thyroid hormones may play a direct role in remyelination and repair in the adult CNS by
promoting maturation of oligodendrocytes. Further, thyroid hormones have been shown to reduce
oxidative stress and thus may have the capacity to prevent mitochondrial dysfunction as well.
Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone
actions, liothyronine (synthetic form of T3) has the potential to induce reparative
mechanisms and limit secondary neurodegeneration in MS. In mice, T3 administration has shown
to help facilitate recovery from cuprizone-induced demyelination. In this study, the
investigators propose to perform a phase 1 study in patients with MS to establish a tolerable
dose of liothyronine, evaluate the safety of this medication, determine whether it impacts
function, and evaluate if it is associated with changes in neurotrophic and/or inflammatory
biomarkers in the cerebrospinal fluid (CSF).

Inclusion Criteria:

- Must meet 2010 McDonald criteria for clinically definite MS

- Must be euthyroid

- Expanded Disability Status Scale (EDSS) 3.0-7.5

- Patients may be on MS immunomodulating therapies or immunosuppressant therapies during
the study

Exclusion Criteria:

- Known thyroid disease (past or current)

- Currently on thyroid replacement therapy

- Steroid use within a month of screening

- History of coronary artery disease, atrial fibrillation, or other clinically
significant cardiac disease

- History of adrenal insufficiency

- Ongoing renal and/or liver disease

- Ongoing severe depression and/or anxiety

- Use of carbamazepine, phenytoin, phenobarbital, warfarin, antacids, cholestyramine,
colestipol, sucralfate, and rifampin

- Known contraindication to using beta-blocker medications

- History of alcohol or substance abuse in the past 6 months

- Pregnant or nursing

- If the investigator feels that participation in this study is not in the best interest
of the subject