Ampyra for Optic Neuritis in MS

Optic neuritis (ON) is the presenting feature of multiple sclerosis (MS) in 15% of cases, and
occurs over the disease course in 50% of patients.1-3 Vision remains a major concern for MS
patients, as visual dysfunction leads to lower quality of life.4-6 Despite the high
prevalence of ON in MS, treatment and management options remain limited. Although intravenous
glucocorticoids are employed to aid recovery of an acute episode of ON, no convincing
evidence supports their efficacy in altering the degree of long-term recovery.7 Although some
individuals with ON can have a dramatic recovery from blindness, ON often impairs visual
function permanently. In the Optic Neuritis Treatment Trial, 63% reported that vision had not
returned to normal after 6 months, and 20% had vision worse than 20/20 after 5 years of
follow-up.8, 9 Visual impairment creates difficulties at home and work, leading to decreased
independence and impaired mobility within the community. Visual dysfunction in combination
with MS impairments within cerebellar and proprioceptive systems can be particularly
disabling.

Optic neuritis classically impairs one's ability to read print or a computer screen, to drive
in bright or low light, and to appreciate colors and contrasts. Unfortunately, when optic
neuritis results in lasting impairment, there are no pharmacologic therapies to restore
vision. Low vision specialists may provide magnifying glasses, brighter lights, and advice to
optimize the position of objects at home and in the workplace. Better treatment options are
needed to improve visual function.

Ampyra (dalfampridine) is a potassium-channel antagonist, with a mechanism-of-action to
improve nerve conduction in demyelinated axons, resulting in an electrophysiologic and
clinical benefit.10-22 Demyelinated axons within the anterior visual pathway would be a prime
and ideal target to study the effects of Ampyra. In fact, Stefoski et al demonstrated visual
function benefit in an open-label study of IV 4-aminopyridine in 12 subjects.21 The optic
nerves are a well-defined white-matter tract, commonly affected in MS, and with clear
clinical outcome measures. In addition, visual evoked potentials (VEPs) can be included
within the study design as a secondary endpoint, to confirm improved nerve conduction.
Because VEPs are such a precise, reliable, and accepted measure of demyelination, the
anterior visual pathway is the ideal in vivo human system to study the electro-physiologic
effects of a therapeutic such as Ampyra.

Hypothesis 1: Dalfampridine treatment will improve visual function, measured by the 5% ETDRS
contrast sensitivity chart, in subjects with long-term visual impairment secondary to optic
neuritis from MS.

Hypothesis 2: Dalfampridine treatment will reduce visual evoked potential P100 latency
following remote optic neuritis.

Hypothesis 3: Dalfampridine treatment will result in an improvement in secondary endpoints,
including visual fields, high contrast visual acuity, color vision, and quality of life.

The study will be conducted at the Department of Neurology and Neurosurgery, Washington
University School of Medicine, St. Louis, the institution at which Dr. Naismith is based. The
MS patients will come from the 1800 active MS patients in our clinic and the 3500 in the St.
Louis area.

Fifty subjects will be enrolled in this Phase II, investigator-initiated, randomized and
blinded cross-over trial of dalfampridine of 8 weeks duration (Table 1). The study will test
the hypothesis that dalfampridine, when administered to subjects with incomplete visual
recovery after optic neuritis from MS, will result in symptomatic improvement in visual
function. The study will consist of one screening/baseline visit, one visit during treatment
with active drug, and one visit on placebo. After the baseline visit, subjects will be
randomly assigned to receive study medication or placebo for the first three weeks, followed
by a two week wash-out, and then treatment reallocation for the latter three weeks.

Inclusion criteria are:

1. At least one previous clinical episode of optic neuritis,

2. the last episode of ON must have occurred at least 12 months prior to study entry,

3. clinically definite MS, defined by the revised McDonald criteria, 23

4. ages 18-70,

5. visual acuity greater than or equal to 20/30

6. must be able to read at least 2 of the 5 letters on the top line of the 5% ETDRS chart
(logMAR 0.96) at 3 meters, 2 meters or 1 meter, and

7. must have sufficient cognitive function to understand the consent process and to
reliably perform all clinical assessments

Exclusion criteria are:

1. Any ophthalmologic condition, other than ON, which can affect vision, including
nystagmus in primary position of gaze,

2. history of seizures or spells with altered level of consciousness,

3. pregnancy or breast feeding,

4. an MS exacerbation or use of glucocorticoids within 3 months of entry,

5. a history of moderate to severe renal insufficiency,

6. previous use of 4-aminopyridine, in any formulation, in the prior 4 weeks.