Acorda is exploring several therapeutic approaches that may help restore function or repair nerve connections in the central nervous system.

Clinical Stage

• Neuregulins – This program is applying Glial Growth Factor 2 (GGF2), a neuregulin growth factor, to stimulate repair in both the nervous and cardiac systems. In published studies in preclinical models, GGF2 has been shown to protect the brain from the consequences of stroke and to stimulate remyelination in models of MS. In addition, neuregulins have shown the ability to restore cardiac function and improve survival in preclinical models of heart failure caused by myocardial infarction, rapid pacing, and viral and chemically induced cardiomyopathies.
  
  Acorda has initiated a Phase 1 single-dose clinical trial of GGF2 in patients with heart failure. The Company is also continuing preclinical studies of potential neurology indications for GGF2 and other neuregulin growth factors.

Preclinical Stage

• Remyelinating antibodies – Studies have demonstrated the ability of this family of antibodies to stimulate remyelination in three different preclinical models of MS. Currently, there is no approved therapy that repairs the lost or damaged myelin in demyelinating diseases such as MS.
• Chondroitinase – This program is based on breaking down inhibitory factors in the scar tissue that develops as a result of an injury to the CNS. Published research has demonstrated that this scar matrix is partly responsible for limiting the regeneration of nerve fibers in the CNS and restricting their ability to modify existing neural connections. Independent academic laboratories have also published preclinical studies showing that application of chondroitinase can result in recovery of function following injuries to various areas of the brain and spinal cord.

 

In the normal brain and spinal cord, nerve cells (neurons) communicate with each other in a giant "telephone network" via the nerve processes (axons). These axons serve as the "wires" that allow nerves to communicate with each other. As in a physical telephone network, the axons are covered with an insulation (myelin) to allow efficient conduction of electrical impulses. Without myelin, the nerves "short circuit" and are no longer able to conduct impulses, so that function mediated by the nerves, including motor strength and walking ability, is diminished or lost. In MS, the immune system attacks the myelin sheath, damaging or destroying it. The body initially can repair its myelin, but at some point in MS, spontaneous repair ceases. Currently, there are no therapies that repair or restore myelin.

In many neurological conditions, the nerves themselves also are damaged or destroyed. Such conditions include MS, spinal cord injuries, traumatic brain injury and stroke, among others. In these cases, restoration of function must rely on regeneration and reconnection of the nerves, something that is not achievable with any current therapy.

Our remyelination programs include both growth factor (neuregulins) and antibody approaches to stimulate repair of damaged myelin.

The cells that make myelin, called oligodendrocytes, have a limited capacity to repair areas of damage in the adult nervous system. Both our lead neuregulin molecule, Glial Growth Factor 2, or GGF2, and our antibody rHIgM22, have been shown in preclincial studies to stimulate oligodendrocytes (the myelin producing cells) and increase repair of areas of demyelination. This process helps to restore electrical conduction and may also serve to protect the exposed nerve fiber from further damage.

Neuregulins

In 2002, Acorda acquired an exclusive worldwide license from CeNeS Pharmaceuticals (now part of Paion AG) to its neuregulins intellectual property and technology related to neuregulins - a class of naturally occurring protein growth factors that have multiple effects on the nervous and cardiovascular systems, and potential therapeutic applications in both.

The most clinically advanced of these agents, Glial Growth Factor 2 (GGF2), is a member of the neuregulin family of growth factors related to epidermal growth factor. The neuregulins bind to erbB receptors, which translate the growth factor signal to the cell and cause changes in cell growth, protein production and gene expression.

These changes have been shown to enhance neuroprotection and repair of nerve tissues, which have led to promising results in a range of preclinical models of disease and injury to both the CNS and peripheral nervous system (PNS):

• Published studies have shown that GGF2 can stimulate remyelination in preclinical models of MS.
• Acorda and its collaborators have demonstrated that neuregulins can protect cells of the substantia nigra in the brain and preserve motor function in preclinical models of Parkinson's disease.
• Neuregulins also have been found to protect the brain and enhance recovery following both transient and permanent ischemia models of stroke.
• In addition, neuregulins protect central and peripheral neurons from chemically induced death and dysfunction, such as following exposure to common chemotherapeutics.

Neuregulins also have been shown to protect heart muscle cells (cardiomyocytes) from a wide range of injuries both in vitro and in vivo. Neuregulins have shown the ability to restore cardiac function in preclinical models of heart failure caused by myocardial infarction, rapid pacing, and viral and chemically induced cardiomyopathies.

We plan to initiate a Phase 1 single-dose clinical trial of the neuregulin GGF2 in patients with heart failure based on an IND filed with the U.S. Food and Drug Administration (FDA) on March 19, 2010. We are beginning the clinical program with a cardiac indication because we believe that "proof of concept" in humans may be studied more efficiently in this indication. However, we are also continuing preclinical studies of potential neurology indications for GGF2 and other neuregulin growth factors.

Remyelinating Monoclonal Antibodies

Acorda’s remyelinating antibody program is based on more than 15 years of research performed at the Mayo Clinic.

Studies have demonstrated the ability of this family of antibodies to stimulate repair of myelin in three different preclinical models of MS. In particular, these antibodies have been found to react with molecules on the surface of oligodendrocytes, the nerve cells that make the myelin sheath, and stimulate them to increase their remyelination activity. These IgM antibodies were first identified in mice and similar antibodies were subsequently identified in human blood samples.

Manufacturing process development and pilot safety and toxicology are under way. Acorda is pursuing scaled up CGMP manufacture of rHIgM22 with a contract manufacture in preparation for future clinical development.

Nerve fibers in the brain and spinal cord have been shown to be capable of self-repair or regeneration, but they are prevented from regenerating following an injury by local inhibitory factors. Among the most potent of these inhibitors are chondroitin sulfate proteoglycans (CSPGs), a component of the scar matrix that forms after injury. Acorda is testing chondroitinase, a bacterial enzyme that has been shown to inactivate CSPG scar and to improve motor and sensory function in preclinical models. The company’s chondroitinase research program includes several behavioral studies that have demonstrated a beneficial effect of chondroitinase on both locomotion and bladder control.

Results of an Acorda study were published in the Journal of Neurotrauma in February 2005. The research shows efficacy of chondroitinase in a clinically relevant model of SCI. In addition, published studies by several university-based researchers have shown that chondroitinase leads to recovery of visual and motor functions after a variety of injuries to the brain or spinal cord.