Safety and Tolerability of Perampanel in Cervical Dystonia

Idiopathic cervical dystonia (CD) is the most common form of focal dystonia with a prevalence
of approximately 60 cases per million population.(Nutt et al.,1988). Current oral medical
treatments for CD have variable efficacy and often with marked side effects. Botulinum toxin
injections may be more effective than pharmacological therapies, and are currently the best
available therapeutic option. However, repeat injections, administered by a physician trained
in this area are required every 3-4 months.(Brans et al.,1996) This can often be difficult
and costly for patients. Furthermore, there are subgroups of patients who simply do not
respond to this treatment and between 5-20% of patients may become secondary non responders
due to the development of blocking antibodies to the botulinum toxin.(Mejia et al., 2005)
Thus, new therapeutic options are required.

The neural mechanisms underlying idiopathic dystonia are not well known. Classical basal
ganglia circuitry models predict underactivity of the output regions of the basal ganglia,
the medial globus pallidus and substantia nigra pars reticulata (;Mitchell et al 1990). In
subjects with dystonia undergoing DBS, intraoperative recordings have demonstrated
underactivity of the medial globus pallidus (Vitek et al, 1999, Lozano et al 1997). One
mechanism responsible for these basal ganglia output changes may be overactivity of
corticostriatal glutamatergic pathways, as similar neural mechanism are thought to underlie
other hyperkinetic movements (Brotchie 2005). The best studied hyperkinetic movement disorder
is levodopa-induced dyskinesia in Parkinson's disease in which dystonia, often of the head
and neck, may occur. In animal models of levodopa-induced dyskinesia, increased striatal
glutamatergic signaling via alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid
(AMPA) receptors has been demonstrated (Perier et al 2002, Silverdale et al 2010). To date
there are few validated animal models of idiopathic dystonia. However, one model that has
been use for pharmacological studies, and the results extrapolated to idiopathic dystonia, is
the paroxysmal dt(sz) dystonic hamster (Loscher and Richter 1998). In this model,
intrastriatal and systemic injection of NBQX a selective AMPA receptor antagonist reduced
dystonic severity (Richter et al 1993, Sander and Richter 2002, Kohling et al 2004). Other
studies have suggested that cerebellar outflow pathways, using AMPA receptors may also
mediate dystonic symptoms. Thus the excitatory amino-acid kainite injected into rodent
cerebellar vermis resulted in dystonic symptoms, an effect revered by NBQX, suggesting an
action on AMPA receptors (Pizoli et al 2002). Thus AMPA receptor antagonists may alleviate
dystonia.

To date, clinical studies using glutamate antagonists in CD have been limited due to lack of
available drugs. A single 6-week open-label pilot study of the non-selective glutamate
antagonist riluzole (50 mg twice a day) in six patients with cervical dystonia (CD) reported
a 26% improvement in CD with no side-effects (Muller et al 2002).

The aim of this study is to conduct a multicentre phase I/IIa open label study to determine
the safety and tolerability of the AMPA antagonist, perampanel in subjects with primary
cervical dystonia. Exploratory analysis will determine effects on dystonia disability and
subjective measures including quality of life and global impression of change. The importance
of such an initial safety study is due to the lack of knowledge related to the use of this
class of drug (AMPA antagonist) in this population of patients. The longer term aim is thus
to generate preliminary data for further randomised controlled efficacy studies.

Inclusion Criteria:

- • 18-65 year old male and female patients with primary cervical dystonia.

- Subject may be untreated with botulinum toxin; treated with botulinum toxin but
who are at least 8 weeks (+ 1 week) from a previous injection; or who have
experienced an insufficient response to botulinum toxin in the opinion of the
enrolling investigator. Note: We will aim to include subjects who have a stable
response that lasts 12 weeks or longer.

- Subjects may be on stable anti-dystonia treatment (for at least one month)
including anticholinergics, baclofen, and anxiolytics including benzodiazepines.

Exclusion Criteria:

- Secondary cervical dystonia,

- Significant dystonia in body areas other than cervical region,

- Cognitive impairment (e.g., Montreal Cognitive assessment (MOCA) < 26);

- Active psychosis;

- History of aggression;

- Active depression (Hamilton Depression Rating Scale (HDRS) score ≥ 12).

- Current abuse of alcohol or subjects who do not agree to avoid alcohol during
treatment,

- Substance abuse (current or prior);

- Active infection,

- Hypersensitivity to perampanel,

- Significant renal dysfunction (Creatinine clearance < 50ml/min),

- Significant laboratory abnormalities (ALT or AST greater than twice normal value;
elevated bilirubin, active liver disease: hepatitis, cholestasis, cirrhosis,
etc.),

- Significant medical illness,

- Women who are pregnant or plan to become pregnant, women who are breastfeeding,

- Subjects who do not agree to avoid consumption of grapefruit or
grapefruit-containing products throughout the study,

- Galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption

- Use of prohibited medications known to be inducers of CYP3A including, but not
limited to: rifampicin, troglitazone, St John's Wort, efavirenz, nevirapine,
barbiturates, glucocorticoids (other than topical usage), modafinil,
pioglitazone, and rifabutin; and any other interactions as per Product Monograph