Trial Information

Phase 3 Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis

Fampridine (4-aminopyridine) is a potassium channel blocker that has been studied since the
1970s for its effect on amplifying conductivity in demyelinated peripheral nerves,
potentiating neurotransmitter release in muscles and increasing post-synaptic action
potentials in the spinal cord. It was tested in various human neurologic conditions over the
next two decades and was found to have a markedly limited therapeutic window due to the
stimulation of seizure activity. Interest in fampridine for treatment of multiple sclerosis
(MS) stemmed from small case series of patients who found therapeutic benefit in many
different neurologic functions including vision, oculomotor function and motor activity. The
first randomized, placebo-controlled, double-blinded study of fampridine in MS in 1992
enrolled 70 patients into a cross over study found significant improvements in a number of
neurophysiological parameters while on fampridine that were not seen in patients while on
placebo. Since then, at least six additional studies on oral fampridine in MS were conducted
and found to have some significant benefits in neurologic function. Although only a small
incidence of seizure or altered mental status were reported in these studies, the concern
about fampridine causing seizures remained a barrier in the acceptance of fampridine as an
MS therapy in the general neurology community.

Recently, Biogen-Idec and Acorda have teamed up in the development of a sustained-release
formulation of fampridine, dalfampridine, which maintains stable plasma concentrations of
the drug and avoids toxic doses that lead to seizures. In two clinical trials, dalfampridine
has been shown to be beneficial in a limited cohort of multiple sclerosis with noted
improvements in gait and lower extremity muscle strength. Seizures were only seen in high
doses of 30 mg twice daily or more whereas benefits were evident at the now standard dose of
10 mg twice daily.

The Food and Drug Administration (FDA) approved dalfampridine for use in multiple sclerosis
in 2009 based on the key study that evaluated the improvement in gait in the responder
cohort of patients rather than the entire study population. This method of analysis focused
on those who reported some benefit from dalfampridine in an initial 4-week trial period and
re-assigned those who did not see benefit to the non-responder group. About 35% of study
subjects fell into the responder group and on average, this group improved their walking
speed by 25%.

The investigators interest in dalfampridine is focused more narrowly on a subset of patients
with a demyelinating disorder that is restricted to the spinal cord. This disorder,
transverse myelitis (TM), was not included in any previous human trials of dalfampridine. In
contrast to MS, which affects the entire central nervous system, this restricted
demyelinating disease affects the spinal cord largely spares the brain and is not associated
with an increased risk of seizures. In addition to being a potentially safer cohort of
patients for dalfampridine, TM is a more homogenous disease model in which to test the
dalfampridine's mechanism of action.

Transverse myelitis, more correctly identified as monophasic idiopathic transverse myelitis
is defined as a single episode of inflammation within the spinal leading to disability at
the level of the lesion and below. The majority of TM lesions strike the thoracic cord
causing impairments in lower extremities and the single lesion is the cause of all of their
symptoms. The goal of using dalfampridine in these patients is to amplify axonal conductance
across this single lesion that would manifest in improved neurologic function involving the
lower extremities including gait. This is the most straightforward proof of concept
experimental model proving the mechanism of action of dalfampridine.