Sunday, June 15, 2008

4-AP, Fampridine-SR, and Spinal Cord Injury

Previously I asked the question - What is 4-Aminopyridine?
Now I'd like to highlight some research which was conducted regarding it's possible use in Spinal Cord Injury(SCI).

Please note that I am not a science professional. I am merely an individual who likes to conduct research and analyze material.

Early Animal Investigation of 4-Aminopyridine (1987-1990):
Andrew Blight*
  • J Neurol Sci, Dec 1987 - Augmentation by 4-aminopyridine of vestibulospinal free fall responses in chronic spinal-injured cats. Blight, Gruner. New York University Medical Center, New York.
  • Brain Res Bull, Jan 1989 - Effect of 4-aminopyridine on axonal conduction-block in chronic spinal cord injury. Blight. New York University Medical Center, New York.
  • J Neurotrauma, Summer 1991 - The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial. Blight, Toombs, Bauer, Widmer. Purdue University School of Veterinary Medicine, Indiana.
First Human Clinical Studies supported by CSRO (1990-1992):
Hayes, Blight, Hansebout, et al.
  • Paraplegia, Apr 1993 - Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury. Hayes, Blight, Potter, Allatt, Hsieh, Wolfe, Lam, Hamilton. Parkwood Hospital, University of Western Ontario, London, Ontario, Canada.
  • J Neurotrauma, Spring 1993 - 4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. Hansebout, Blight, Fawcett, Reddy. McMaster University, Hamilton, Ontario, Canada.
  • J Neurotrauma, Aug 1994 - 4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. Hayes, Potter, Wolfe, Hsieh, Delaney, Blight. Parkwood Hospital, University of Western Ontario, London, Ontario, Canada.

In March 1995, Dr. Ron Cohen founded Acorda Therapeutics, Inc. to develop therapeutic products for spinal cord injury and other central nervous system disorders. In 1995, The Canadian Spinal Research Organization (CSRO) entered into a licensing agreement with Acorda Therapeutics whereby Acorda obtained the rights from CSRO (patent originally obtained by Hansebout and Blight) to develop fampridine for therapeutic use in SCI. To start the more rigorous and official FDA approval process and preclinical development, Acorda also submitted an Investigational New Drug application (IND) in 1995.

  • J Neurotrauma, Mar 1997 - Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury. Qiao, Hayes, Hsieh, Potter, Delaney. University of Western Ontario, London, Canada.
  • Neuroscience, Mar 1997 - Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord. Shi, Blight. University of North Carolina at Chapel Hill.
  • Exp Neurol, Dec 1997 - Conduction block in acute and chronic spinal cord injury: different dose-response characteristics for reversal by 4-aminopyridine. Shi, Kelly, Blight. University of North Carolina at Chapel Hill.
  • Spinal Cord, Mar 1998 - Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases. Potter, Hayes, Hsieh, Delaney, Segal. Parkwood Hospital, London, Ontario, Canada.

Between 1993-1995, Joseph G Masterson of London, UK and Michael Myers of Athlone, IE applied for U.S. Patents related to the sustained-released technology for Fampridine-SR (slow-release fampridine/4-aminopyridine). These patents were assigned to Elan Corporation, plc. The three patents were awarded on December 6, 1994, July 30, 1996, and December 3, 1996.

In January 1997, Acorda entered into another licensing agreement with Elan Corporation plc of Athlone, Ireland, to develop Fampridine-SR for treatment of Spinal Cord Injury. Elan will continue to manufacture and then supply Fampridine-SR to Acorda.

From the February 20, 1997 Announcement:

Dr. Cohen [President and CEO of Acorda] added: "We are delighted to be working with Elan on the development of fampridine for SCI. Elan is a world-leader in drug formulation technology, and we believe that their unique sustained-release formulation of fampridine is a significant advance in administering this compound in chronic SCI. In addition, Elan has superb expertise in leading-edge neurological drug development through their Athena Neurosciences division, which complements Acorda’s teams of world-leading scientists and clinicians in the areas of spinal cord repair and regeneration. Elan’s patented formulation of fampridine also is complementary to Acorda’s patents, which relate to uses of 4-AP in spinal cord injury."

Michael Sember, Vice President of Planning, Investments and Development at Elan, said: "Elan is most pleased to be collaborating with Acorda. We believe that this collaboration offers great potential to accelerate the clinical development of fampridine, as Elan continues to focus on its target markets such as MS, and Acorda carries the product forward for SCI." Mr. Sember has been elected to Acorda’s board of directors as part of the announced deal.
On June 2, 1997, Fampridine-SR was awarded Orphan Drug Designation for treatment of Spinal Cord Injury. In October 1997, Acorda Therapeutics was awarded $2M Advanced Technology Program (ATP) for Spinal Cord Regeneration Project.

Phase II Trials and Pharmacokinetics Studies (1997-2001):
Hayes, Potter, Hansebout, Blight, et al.

  • J Neurotrauma, Oct 1998 - Randomized double-blind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury. Potter, Hayes, Segal, Hsieh, Brunnemann, Delaney, Tierney, Mason. Parkwood Hospital, University of Western Ontario, London, Canada.
  • Spinal Cord, Jan 2000 - Intravenous infusion of 4-AP in chronic spinal cord injured subjects. Donovan, Halter, Graves, Blight, Calvillo, McCann, Sherwood, Castillo, Parsons, Strayer. The University of Texas Houston Medical School, Houston, Texas.
  • J Clin Pharmacol, Apr 2000 - Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury. Segal, Hayes, Brunnemann, Hsieh, Potter, Pathak, Tierney, Mason. Department of Veterans Affairs Medical Center, Long Beach, California.
  • Spinal Cord, Dec 2000 - Intrathecal administration of 4-aminopyridine in chronic spinal injured patients. Halter, Blight, Donovan, Calvillo. Baylor College of Medicine, Houston, Texas.
  • J Neurotrauma, Aug 2001 - Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial. 26 patients. Wolfe, Hayes, Hsieh, Potter. University of Western Ontario, London, Canada.
  • J Clin Pharmacol, Apr 2003 - Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury. Hayes, Katz, Devane, Hsieh, Wolfe, Potter, Blight. University of Western Ontario and Lawson Health Research Institute, London, Ontario, Canada.
  • Clin Neuropharmacol, Jul-Aug 2003 - Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury. Hayes, Potter, Hansebout, Bugaresti, Hsieh, Nicosia, Katz, Blight, Cohen. University of Western Ontario and Lawson Health Research Institute, London, Ontario, Canada.
  • Arch Phys Med Rehabil, Jan 2004 - Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury. Hayes, Potter, Hsieh, Katz, Blight, Cohen. University of Western Ontario and Parkwood Hospital, London, Canada.
  • Spinal Cord, Feb 2007 (epub Jun 2006) - Phase 2 trial of sustained-release fampridine in chronic spinal cord injury. Cardenas, Ditunno, Graziani, Jackson, Lammertse, Potter, Sipski, Cohen, Blight. University of Washington, Seattle.
In August 2003, Acorda entered an Amended & Reinstated License Agreement with Canadian Spinal Research Organization (CSRO) for SCI.

Discussion of Clinical Trials and use of Fampridine in SCI & MS

  • Curr Opin Investig Drugs, Nov 2000 - Fampridine Acorda Therapeutics. Darlington. University of Otago, Dunedin, New Zealand.
  • Curr Opin Investig Drug, Jun 2001 - Acute spinal cord injury: pharmacotherapy and drug development perspectives. Blight, Zimber. Acorda Therapeutics Inc., Hawthorne, New York.
  • CNS Drug Rev, Winter 2004 - The use of 4-aminopyridine (fampridine) in demyelinating disorders. Hayes. University of Western Ontario, London, Ontario, Canada.
  • J Neurotrauma, Mar-Apr 2006 - Clinical trials in spinal cord injury. Blight, Tuszynski. Acorda Therapeutics, Hawthorne, New York.
  • Mult Scler, Apr 2007 - Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study. Goodman, Cohen, Cross, Vollmer, Rizzo, Cohen, Marinucci, Blight. University of Rochester, Rochester, New York.
  • Expert Rev Neurother, May 2007 - Fampridine-SR for multiple sclerosis and spinal cord injury. Hayes. University of Western Ontario, London, Ontario, Canada.
Phase III Clinical Trials of Fampridine-SR in Treatment of SPI:
  • June 28, 2002 - Acorda Therapeutics announced today that it has begun two Phase 3 clinical studies of its lead product, Fampridine-SR, in chronic spinal cord injury.
  • April 14, 2004 - Acorda Therapeutics announced today initial results of both a Phase 2 clinical trial of its lead product candidate, Fampridine-SR, in people with multiple sclerosis (MS), and two Phase 3 trials in people with chronic spinal cord injury (SCI). Data from the MS trial showed a strong positive trend in improvement of walking speed and a significant improvement in leg muscle strength, the trial’s primary and secondary endpoints. Data from one of the two SCI trials showed a strong positive trend in a primary endpoint of reducing muscle spasticity, but neither SCI trial achieved statistical significance in its primary endpoints. Acorda plans to meet with the U.S. Food and Drug Administration (FDA) to discuss a potential Phase 3 trial of Fampridine-SR in MS and further development for SCI.

After the disappointing results of the Phase III SCI trials, Acorda put their Fampridine-SR and SCI project on hold to focus more resources on the Fampridine-SR and MS project.

*Brief Bio of Andrew Blight:

Andrew R. Blight, Ph.D., has been our Chief Scientific Officer since January 2004 and previously served as our Executive Vice President, Research and Development from 2000 to 2004, and Vice President, Research and Development, from 1998 to 2000. Prior to joining Acorda, Dr. Blight spent approximately six years as Professor and Director of the Neurosurgery Research Laboratory at the University of North Carolina at Chapel Hill. Dr. Blight held prior academic positions at Purdue University and New York University. Dr. Blight is a leader in SCI pathophysiology research and has made several important contributions to the field, particularly on the role of demyelination in SCI. He also pioneered the therapeutic application of 4-AP in SCI animal models and in human clinical trials. Dr. Blight is a member of the editorial board of the Journal of Neurotrauma and has served as a member of the NIH NSDA review committee. He was previously Secretary, Treasurer and Vice President of the National Neurotrauma Society. Dr. Blight received his B.S. in Zoology and his Ph.D. in Zoology/Neurobiology from the University of Bristol, U.K.

Next time, I'll discuss more on the research regarding Fampridine-SR and MS.

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