Open-Trial of EPI-743 for Adults With Tourette Syndrome

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by
multiple motor and vocal tics that last for at least a year in duration. Currently, there
exist several effective pharmacological treatments for childhood tics including alpha-2
agonist medications (guanfacine and clonidine) and neuroleptics (antipsychotic) medications.
These medications, however, have significant side-effects and are only partially effective
in treating tics.

EPI-743 is an orally absorbed small molecule that readily crosses into the central nervous
system. It works by targeting an enzyme NADPH quinone oxidoreductase 1 (NQO1). Its mode of
action is to synchronize energy generation in mitochondria with the need to counter cellular
redox stress. EPI-743 has recently received orphan drug status from the U.S. Food and Drug
Administration (FDA). The FDA has allowed an Expanded Access program to provide EPI-743 to
seriously ill patients diagnosed with inherited respiratory chain diseases of the
mitochondria.

The rationale for the use of this agent is indirect. Over the past 10 years, defects in
mitochondrial oxidative phosphorylation (OXPHOS) have been implicated in a wide variety of
neurodegenerative and neuromuscular diseases. One neurological symptom that has definitely
been associated with OXPHOS is the movement disorder dystonia. A specific missense mutation
in the mtDNA complex I (NADH dehydrogenase) gene, MTND6, has been linked to maternally
inherited dystonia along with the companion phenotype, Leber's hereditary optic neuropathy.
In addition, other mitochondrial diseases are also associated with movement disorders
including Friedreich's ataxia (ataxia) and Leigh's disease (loss of head control and other
motor skills). EPI-743 has been effective in treating children and adults with these
diseases. Over time, many TS patients develop complex motor tics, which are sudden, more
purposive appearing, stereotyped movements of variable duration. Examples are myriad and
include facial gestures and movements such as brushing hair back, possibly in combination
with head jerk, and body shrugs. Gyrating, bending, and twisting movements of the head or
torso are also seen. These slow twisting movements are usually referred to as dystonic tics.

A second line of evidence concerns the potential therapeutic value N-acetyl-cysteine (NAC)
in the treatment of neuropsychiatric conditions closely related to TS including
Trichotillomania (TTM) and Obsessive-compulsive disorder [OCD]. Recent double-blind,
placebo-controlled studies of NAC have provided evidence of efficacy in reducing the
symptoms of trichotillomania (TTM) in adults [49]. The effect size in this 12-week study was
strikingly large (d = 1.3). Trichotillomania, like TS, is considered to be an
obsessive-compulsive spectrum disorder. Individuals with TTM experience urges prior to
hairpulling, similar to the urges in TS. Case reports have also suggested the potential
efficacy of NAC in treating OCD. NAC is hypothesized to have two possible mechanisms of
action. NAC is converted to cystine, a substrate for the glutamate/cystine antiporter
located on glial cells. The uptake of cystine by glia causes the release of glutamate into
the extrasynaptic space, where it stimulates inhibitory metabotropic glutamate receptors on
glutamatergic nerve terminals and thereby reduces the synaptic release of glutamate. NAC is
also a precursor of glutathione, the major antioxidant in the brain. Through this mechanism
NAC is hypothesized to improve OXPHOS. One effect of EPI-743's activity on NQO1 is
restoration of cellular glutathione stores.

A third line of indirect evidence is that in postmortem brain studies, the two classes of
interneurons that are reduced in number in the basal ganglia are "high energy" consuming
cells, i.e., GABAergic, fast spiking internerons and cholinergic tonically active
interneurons. Given the high energy demand associated with these cells perhaps their loss is
partially due to defects in OXPHOS.

A fourth line of indirect evidence is that when EPI-743 is effective in treating
mitochrondrial disease, brain regions with very low HMPAO uptake show a marked increase in
uptake. In the case of TS (50 cases and 20 controls) HMPAO uptake was found to be reduced in
the left caudate, anterior cingulate cortex and the left dorsolateral prefrontal cortex.
Severity of tics was related to hypoperfusion of the left caudate and cingulate and a left
medial temporal region.

Inclusion Criteria:

- Adult between 18-65 years of age

- Meet DSM IV criteria for the diagnosis of Tourette's syndrome

- Significant current tic symptoms: YGTSS total tic score greater than or equal to 22
at baseline

- On stable psychiatric medication regimen for a minimum of 4 weeks prior to beginning
the trial.

- Accepted method of birth control

- Willingness to participate in an HMPAO SPECT scan at baseline and after 4 weeks of
treatment.

Exclusion Criteria:

- Comorbid bipolar disorder, psychotic disorder, substance use disorder, developmental
disorder or intellectual disability (IQ<70).

- Recent change (less than 4 weeks) in medications that have potential effects on tic
severity. Medication change is defined to include dose changes or medication
discontinuation.

- Recent change in behavioral treatment for Tourette syndrome or comorbid conditions
(i.e. OCD) within the last 4 weeks or initiation of behavioral therapy for tics
within the last 12 weeks.

- Known hypersensitivity or previous anaphylactoid reaction to EPI-743 or any
components in its preparation

- Positive pregnancy test or drug screening test

- Clinical history of bleeding disorder or abnormal baseline PT/PTT

- Hepatic insufficiency with LFTs greater than two times upper limit of normal