The FDA and Acorda Therapeutics Inc. have aligned pivotal development plans for Fampridine-SR (4-aminopyridine) in multiple sclerosis after reaching agreement on a special protocol assessment.
The resulting Phase III study, scheduled to begin in about a month, is designed to show that Fampridine-SR-treated patients are significantly more likely to have consistent improvements in their walking ability than those treated with placebo. Its primary endpoint will measure improvements through two evaluations, the objective Timed 25-Foot Walk and the subjective Multiple Sclerosis Walking Scale-12 (MSWS12).
Acorda President and CEO Ron Cohen noted that no current treatments improve walking in multiple sclerosis patients despite observations that it is one of the areas of greatest unmet medical need for the condition.
"It's a novel indication," he said, "and we wanted to make absolutely sure that the agency and we agreed on how to prove that through a clinical trial in a way that would lead to a new drug application, if the trial were successful."
Secondary outcome measures for the study include the Lower Extremity Manual Muscle Test (LEMMT), a standardized, five-point manual assessment of leg strength, as well as the Ashworth score for spasticity and global impressions.
"Walking subsumes so many central nervous system functions," Cohen told BioWorld Today. "It's motor function, sensory function, position sense, balance and even visual function."
The company, of Hawthorne, N.Y., noted that multiple sclerosis is characterized by frequent waxing and waning of a patient's walking ability, strength and other neurological functions. The coming year-long study, likely to be the first of two trials needed for regulatory submission, will enroll about 240 patients into two arms: two daily doses of Fampridine-SR 10 mg or placebo. The trial will amount to a response analysis, with evaluations of patients' abilities to consistently walk faster over a three-month period than at any time when they are not taking the drug during the study.
"We will look to see if the drug-treated patients statistically have a more consistent improvement in speed [compared to placebo patients]," Cohen said, adding that responses differ daily due to temperature changes and other environmental conditions that impact the disorder. "MS is a very variable condition, so we expect even the placebo patients to go up and down during the course of our study."
Results from the most recent Phase II trial showed a positive trend for improvement in average walking speed, as measured by the Timed 25-Foot Walk, and a statistically significant improvement in LEMMT. A post-hoc analysis, using the methods to be applied in the Phase III study, showed an increase in the number of subjects with consistently improved walking speed in the Fampridine-SR-treated group compared to placebo. Acorda called the data consistent with results of earlier Phase II trials.
"What we've shown in our previous study," Cohen said, "is that patients who are consistent responders on the Timed 25-Foot Walk also have a statistically significant improvement in their MSWS12 vs. the non-responders, meaning that patients who are responding consistently on the Timed 25-Foot Walk also recognize subjectively that their walking is overall better in their day-to-day lives."
Fampridine-SR, a tablet that employs sustained-release technology from Elan Corp. plc, in lab studies improved impulse conduction in nerve fibers in which myelin has been damaged. The drug also has been developed for spinal cord injury, though that program remains on hold - a little more than a year ago, Fampridine-SR missed endpoints of reducing spasticity and improving spinal cord injury patients' Subject Global Impression ratings in two pivotal Phase III trials. (See BioWorld Today, April 15, 2004.)
"Because we had a good Phase II result in MS, we needed to focus all our resources to getting into Phase III," Cohen said, adding that one of the Phase III studies in spinal cord injury was far closer to proving efficacy than the other. "We plan to go back into those data and look for explanations as to why they didn't come out the way we hoped."
Should those evaluations define a path forward for that program, Acorda would again pick up the spinal cord injury baton.
The company owns worldwide development and marketing rights to the drug through a license and supply agreement with Elan, and all efforts are focused on the U.S. and Canadian markets. Cohen said Acorda is engaged in talks to partner the product outside North America.
Beyond its Fampridine-SR activities, the company markets a single product, Zanaflex capsules (tizanidine hydrochloride), a short-acting drug indicated for the management of spasticity. It also gained rights to the product from Elan, of Dublin, Ireland. (See BioWorld Today, July 30, 2004.)
Elsewhere in Acorda's portfolio is a trio of preclinical products. Cohen was especially enthusiastic about one, a chondroitinase enzyme that degrades inhibitory substances in the brain and spinal cord that prevent regeneration after injury. Independent labs have published positive results from cat and rat models, and the company expects to move it into clinical studies in the next 18 to 24 months. Acorda also has a remyelinating antibody program and a program focused on the neuregulin class of protein growth factors, both of which it would likely look to out-license or partner.