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. Dalfampridine is a sustained-release formulation of fampridine being developed by Biogen-Idec and Acorda that avoids toxic doses that potentially 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%.
Our 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. Transverse myelitis is defined as a single episode of inflammation within the spinal cord leading to disability at the level of the lesion and below. The majority of TM lesions strike the cervical or thoracic cord causing impairments in lower extremities and the single lesion is the cause of all of their symptom.
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. 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.Although dalfampridine is not currently approved for TM, we believe TM patients have a high likelihood of responding positively in their gait to dalfampridine, similar to MS.
The clinical trial that we propose to conduct will focus on monophasic TM and will evaluate the efficacy of dalfampridine in both our primary neurologic outcome, 25-foot timed walk, and several secondary outcomes including validated behavioral and neurophysiological measures. To better understand the mechanisms underlying the proposed behavioral gains, we will use Transcranial Magnetic Stimulation as our neurophysiologic measure to identify changes in corticomotor excitability in the spinal cord.
As of August 2015, subjects are still being tested. Results are expected to be published in the next few years.