Researchers have shown that, contrary to a popular belief, the majority of patients with SCI do not have severed cords. Most SCI victims have blunt damage to the cord; such people usually have some axons that survive the injury and that continue to traverse the injured area. For this reason, most people with SCI retain some limited functions below the level of their injury. However, surviving axons often are partially damaged and lose part of their myelin, the insulating sheath which permits electrical impulses to be conducted down the axon. Nerve impulses "short circuit" when they reach an area of the axon that is demyelinated, much like electricity in a wire whose insulation is stripped. Thus, even though a demyelinated axon is alive, it cannot transmit motor or sensory impulses and the patient effectively loses the use of it.

4-AP’s major action is to block specialized potassium channels found on axons. These potassium channels normally terminate a nerve impulse as it passes through the axon—analogous to a damper on a vibrating piano wire—so that the axon is "reset" and ready to transmit another impulse. When an axon is demyelinated after injury, many more potassium channels than normal are exposed to the environment; rather than simply resetting the axon, therefore, they "overdamp it," preventing it from transmitting any more impulses. By blocking the exposed potassium channels, 4-AP permits the axon to transmit impulses again, even in a demyelinated state.

In numerous in vitro and animal studies, 4-AP has been shown to increase nerve conduction in impaired axons, and to result in improved neurological function. Several initial human trials of 4-AP have also been conducted to date, involving a total of about 100 human subjects with chronic SCI. These trials have reported improvements in a variety of impaired functions. Depending on the specific patient, these improvements have included increased motor, sensory, bladder, bowel and/or sexual functions, as well as reductions in muscle spasticity and/or chronic pain.

The Company will conduct a Phase II clinical trial of 4-AP in the U.S. in the fall of 1997. If this trial is successful, the Company expects to begin pivotal Phase III trials in 1998. A team of the leading academic SCI rehabilitation centers in the U.S. and Canada is working with the Company to design and conduct the 4-AP trials.

How Does Fampridine Work?

Fampridine is the first compound to show promise in restoring some neurological function to people with SCI. So how does it work?


Most people with a spinal cord injury have some axons, or nerve processes, that survive the injury. However, these surviving axons are often damaged and lose part of their myelin, which is the insulating sheath that permits electrical impulses to be conducted down the axon. When the myelin is damaged ("demyelinated"), large numbers of potassium channels are exposed and "leak" potassium ions, causing the axon to "short circuit." Even though a demyelinated axon is alive, it cannot transmit sensory impulses or motor signals from the brain to their ultimate destinations, and the individual effectively loses the use of the axon.


Fampridine counteracts the effects of demyelination. Fampridine-SR restores the ability of damaged nerves to conduct electrical impulses in people with chronic SCI by blocking exposed potassium channels in demyelinated axons. The sustained release (SR) formulation also allows a gradual release of fampridine over a prolonged period of time and maintains a more constant level in the blood.


 

Currently, there is no approved therapy that improves neurological function for individuals with chronic SCI. However, participants with chronic SCI in Phase 2 clinical trials of Fampridine-SR have shown improvement in a variety of impaired neurological functions, including reduced stiffness or spasticity, increased bladder and bowel control, and increased sexual function. When appropriate doses are administered, side effects are reported as mild to moderate, similar to those reported when taking a placebo.
 

Myelinating Monoclonal Antibodies ("M1"). Acorda has an exclusive worldwide license from the Mayo Clinic for a class of proprietary monoclonal antibodies (MAb’s) which stimulate remyelination of CNS axons. The core patent for this technology issued in the U.S. in 1996, and international patents are pending. M1 has been shown to be effective in three different models of demyelination in animals: one caused by a virus, one by an autoimmune reaction, and the third chemically-induced. Two of these models also are widely used to predicting responses in multiple sclerosis (MS). In all three types of demyelination, mice treated with M1 recovered neurological function, such as the ability to walk, and had significantly increased survival relative to the control animals. Thus, the M1 technology has demonstrated the potential to restore neurological function in patients whose axons have been demyelinated (see "4-AP" above), particularly patients with MS and SCI. These patients comprise markets of over 500,000 individuals in the U.S. and Canada alone.

Acorda is currently working to humanize the M1 antibody and to complete preclinical toxicolgy studies necessary for initiating human clinical trials. The Company also is seeking corporate partners to assist in commercializing the M1 technology for MS markets worldwide, and is currently in discussions with such potential partners.

Axonal guidance protein (L1). Acorda has obtained exclusive, worldwide licenses from two universities to patent applications on the uses of L1 and related proteins in the regeneration of central nervous system (CNS) axons. Scientists have discovered that myelin (the "white matter") in the normal brain and spinal cord contains substances which strongly inhibit the growth of axons. Successful regeneration in SCI requires that axons grow out of the spinal cord at one end of the injured area, through the injured area itself, and then into the cord at the opposite end of the injured area, where they may reestablish connections. Over the past decade, scientists have achieved substantial regrowth of spinal axons by applying a variety of nerve growth factors to the site of injury. However, these axons generally have not grown far enough because substances within the white matter have blocked further growth.