4-AP, Fampridine-SR, and Multiple Sclerosis

If you are just joining the conversation, first read What is 4-Aminopyridine? and 4-AP, Fampridine-SR, and Spinal Cord Injury.

In 1990, Elan Corporation, plc licensed from Rush-Presbyterian Hospital in Chicago the Know-How related to fampridine (4-aminopyridine) for symptomatic treatment of multiple sclerosis. By 1997, Elan Corporation, plc had obtained three U.S. patents related to the sustained-released technology for Fampridine-SR (slow-release fampridine/4-aminopyridine).

Clinical Research at University of Maryland, Baltimore (1990-97):

Bever, Leslie, Panitch, et al. Studies sponsored by Elan.

• Ann Neurol, April 1990 - Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis. 10 patients. Bever Jr, Leslie, Camenga, Panitch, Johnson. University of Maryland School of Medicine, Baltimore.
• Ann Neurol, 1994 - The current status of studies of aminopyridines in patients with multiple sclerosis. Bever Jr. University of Maryland School of Medicine, Baltimore.
• Neurology, Jun 1994 - The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial. 8 patients. Bever Jr, Young, Anderson, Krumholz, Conway, Leslie, Eddington, Plaisance, Panitch, Dhib-Jalbut, et al. University of Maryland Hospital, Baltimore.
• Neurology, Dec 1996 - Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, placebo-controlled, crossover trial. 36 patients. Bever Jr, Anderson, Leslie, Panitch, Dhib-Jalbut, Khan, Milo, Hebel, Conway, Katz, Johnson. University of Maryland School of Medicine, Baltimore.

First Clinical Trials of Fampridine-SR in MS (1997):

Schwid, Goodman, Bever, et al. Studies sponsored by Elan.

• Neurology, Apr 1997 - Quantitative assessment of sustained-release 4-aminopyridine (EL-970) for symptomatic treatment of multiple sclerosis. 10 patients. Schwid, Petrie, McDermott, Tierney, Mason, Goodman. University of Rochester Medical Center, Rochester, New York.
• Long-term study abruptly termindated, thus incomplete and unpublished - Bever Jr, et al. University of Maryland School of Medicine, Baltimore, Maryland.

In April 1998, Acorda Therapeutics, Inc. and Elan EIS entered a joint venture and formed the MS Research & Development Corp (MSRD). MSRD turned around and licensed research and development technology from Elan to develop Elan's proprietary oral sustained release formulation of fampridine for the treatment of multiple sclerosis. MSRD was permanently terminated in September 2003. [*see explanation below]

Regarding Compounding Pharmacies and Bulk Drug Lists

Prior to the Food and Drug Administration Modernization Act of 1997, 4-aminopyridine was available from compounding pharmacies in the U.S. This new legislation specified that "a drug product may be compounded under subsection (a) if the licensed pharmacist or licensed physician-- '(A) compounds the drug product using bulk drug substances,..."

A letter dated June 4, 1998 submitted by a board member of the South Carolina Board of Pharmacy nominated 21 bulk drug substances as candidates for the bulk drug list, including 4-aminopyridine. The package submitted includes a review of safety and efficacy data, including peer reviewed medical literatureune of 4-AP (see pages 1-61).

During a May 1999 FDA meeting (read transcript beginning p.40) discussing candidates for the national bulk drug list, Dr. Bever was questioned extensively regarding the long-term trial he was conducting for Elan which was abruptly terminated. A panelist for the FDA asked a representative of Elan, "compounded products have significant risk for adverse effects, but, yet, your company took a group of patients who was on your product and hung them out to dry. Why did that happen?" (see page 72)

Later during the meeting, Dr. Cohen summed up his objection to including Aminopyridine on the Bulk Drug List.

"If pharmacy compounded fampridine continues to be made available, we would not be able to justify the significant additional investment of time and resources that an expanded access study would require. Moreover, we would have to seriously review whether it would be economically feasible for us to continue clinical development of this compound. We believe that such an outcome would poorly serve the long-term interest of the patients and their healthcare providers, who deserve to have a therapy that can be prescribed with assurance of reliable dosing, appropriate indications for use and overall safety and efficacy. Such assurance can only be obtained for this drug if it is developed under INDs and approved by FDA under an NDA." - Dr. Cohen

During a June 13, 2000 FDA meeting (read transcript beginning p.20) discussing updates to the Acorda's promised Expanded Access Study of Fampridine which never happened. A question from the panel was "Are you more interested in patients with MS or spinal cord injuries?"

"Well, as a company, we were founded primarily to develop therapies for spinal cord injury, but because of our interest in demyelination in spinal cord injury, we have broadened that to include MS. So, we are now equally interested in both conditions, although our roots are in the spinal cord injury side of this." - Dr. Blight (p.28)

Phase II Clinical Trials (2000-04):

In December 2000, Accorda announced they would Initiate Phase II Trial of Fampridine-SR in MS (MS-F201). Results of that trial were presented at the Sept 2002 ECTRIMS meeting but weren't published until 2007.

• Mult Scler, April 2007 - Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study. 36 patients. Goodman, Cohen, Cross, Vollmer, Rizzo, Cohen, Marinucci, Blight. University of Rochester Medical School, Rochester, New York. (MS-F201)
• Nat. SPI Assoc, April 14, 2004 - Acorda Therapeutics Reports Results of Fampridine-SR Clinical Trials. 200 patients. Goodman, et al. University of Rochester Medical School, Rochester, New York. (MS-F202)

Phase III Clinical Trials (2005-08):

May 30, 2005 - Announce Special Protocol Assessment (SPA) for Phase III
Sep 26, 2006 - Announce Positive Phase III Results in MS ; results presented at AAN meeting on May 2, 2007 (MS-F203)

Jan 28, 2008 - Announce Successful QT Safety Study
Mar 25, 2008 - Announce Survey Results Mobility Quality of Life
Jun 2, 2008 - Announce Positive 2nd Phase III Results in MS (MS-F204)

Studies designed to develop and improve quantitative functional measures for use in determining disease progression or symptomatic improvement (1997-2002): Schwid, Goodman, et al. Rochester.

• Neurology, Nov 1997 - The measurement of ambulatory impairment in multiple sclerosis. Schwid, Goodman, Mattson, Mihai, Donohoe, Petrie, Scheid, Dudman, McDermott. University of Rochester Medical Center, Rochester, New York.
• Neurology, Sep 1999 - Quantitative assessment of motor fatigue and strength in MS. Schwid, Thornton, Pandya, Manzur, Sanjak, Petrie, McDermott, Goodman. University of Rochester Medical Center, Rochester, New York.
• Neurology, Dec 2000 - Are quantitative functional measures more sensitive to worsening MS than traditional measures? Schwid, Goodman, Apatoff, Coyle, Jacobs, Krupp, Miller, Wende, Brownscheidle. University of Rochester Medical Center, Rochester, New York.
• Arch Neurol, Jun 2001 - Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial. Cohen, Cutter, Fischer, Goodman, Heidenreich, Jak, Kniker, Kooijmans, Lull, Sandrock, Simon, Simonian, Whitaker. The Mellen Center, The Cleveland Clinic Foundation, Cleveland, Ohio.
• Neurology, April 2002 - Quantitative functional measures in MS: what is a reliable change? 20% change can be considered a reliable threshold to indicate true change in function for an individual. Schwid, Goodman, McDermott, Bever, Cook. University of Rochester Medical Center, Rochester, New York. Sponsored by NMSS. Presented at Sept 2002 ECTRIMS meeting.

Review of Potassium Channel Blockers in MS (2002-07):
Hayes, Judge, Bever Jr, et al.

• Curr Opin Investig Drugs, Nov 2000 - Fampridine Acorda Therapeutics. Darlington. University of Otago, Dunedin, New Zealand.
• Mol Pharmacol, April 2002 - Determinants of 4-aminopyridine sensitivity in a human brain kv1.4 k(+) channel: phenylalanine substitutions in leucine heptad repeat region stabilize channel closed state. Judge, Yeh, Goolsby, Monteiro, Bever Jr. VA Maryland Health Care System, Baltimore.
• CNS Drug Rev, Winter 2004 - The use of 4-aminopyridine (fampridine) in demyelinating disorders. Hayes. University of Western Ontario, London, Ontario, Canada.
• Pharmacol Ther, July 2006 - Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Review to Date. Judge, Bever JR. VA Maryland Health Care System, Baltimore.
• J Rehabil Res Dev, Jan-Feb 2006 - Voltage-gated potassium channels in multiple sclerosis: Overview and new implications for treatment of central nervous system inflammation and degeneration. Judge, Lee, Bever Jr, Hoffman. VA Maryland Health Care System, Baltimore.
• Expert Rev Neurother, May 2007 - Fampridine-SR for multiple sclerosis and spinal cord injury. Hayes. University of Western Ontario, London, Ontario, Canada.
• Recent Patents in CNS Drug Discov, Nov 2007 - Potassium channel blockers and openers as CNS neurologic therapeutic agents. Judge, Smith, Stewart, Bever Jr. University of Maryland School of Medicine, Baltimore.

*In April 1998, the Company [Acorda] issued to Elan 2,300,000 shares of Series F, at a per share price of approximately $5.22, for aggregate proceeds of approximately $12 million. Also, in April 1998, the Company entered into a joint venture agreement with Elan. The $12 million proceeds from the sale of the Series F was then transferred to MS Research and Development Corp. (MSRD), a joint venture company of which the Company owned approximately 80% and Elan owned 20%, approximately. To purchase its approximate 20% interest, Elan invested an additional $3 million into MSRD. The combined $15 million was subsequently used to license research and development technology from Elan to develop Elan's proprietary oral sustained release formulation of fampridine for the treatment of multiple sclerosis. This purchase is recorded as a license payment expense in the consolidated financial statements for the fiscal year ended June 30, 1998. For the years ended June 30, 2001, 2002 and 2003, and the period from March 17, 1995 (inception) to June 30, 2003, MSRD incurred approximately $2.2 million, $2.9 million, $3.2 million, and $24.6 million, respectively, in research and development expenses, which is included as research and development expense in the accompanying statements of operations, of which Acorda funded 80% and Elan funded 20% until June 30, 2002, in accordance with the terms of the original development agreement. Elan's ownership interest in MSRD is reflected as minority interest in the accompanying statement of operations. The minority interest share of the MSRD losses were being funded by Elan, and through June 30, 2002 the Company received $1,279,361 as a reimbursement of this funding. In fiscal 2003, Elan ceased funding its approximately 20% share of its minority interest in MSRD and the Company ceased recognizing the related minority interest benefit resulting in an increase in the Company's ownership interest to 83% pursuant to the original agreement. [from 2003 S-1 IPO application]