Product Spotlight - Ampyra

Ampyra (dalfampridine) is a potassium channel blocker taken orally as a treatment to improve walking in patients with multiple sclerosis (MS). Ampyra, previously referred to as Fampridine-SR, is provided in an extended-release tablet formulation of dalfampridine, which was previously called fampridine. The name was changed to dalfampridine to avoid confusion with other FDA-approved products.

The efficacy of dalfampridine for this indication was demonstrated by an increase in walking speed. The product was granted orphan drug status, providing 7 years of market exclusivity.

Dalfampridine can be used alone or with existing MS therapies, including immunomodulator drugs. The dose regimen is a 10-mg tablet twice daily, approximately 12 hours apart.

The safety and efficacy of dalfampridine was established in two phase 3 trials that used a responder analysis to determine the effect of treatment on walking speed.

This First Report­–Managed Care Product Spotlight provides a summary of results published from the first trial of dalfampridine to improve walking speed in patients with MS. Data from the second phase 3 trial had not been published at press time.

PHASE 3 TRIAL
Below is summary of a phase 3 trial that compared the efficacy and safety of dalfampridine and placebo to improve ambulatory deficits in patients with MS. Primary data from this clinical trial were first presented at the 2007 American Academy of Neurology annual meeting.

Reference: Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomized, double-blind, controlled trial. Lancet. 2009;373:732-738.

Study Objectives: The trial was designed to evaluate the safety and efficacy of dalfampridine for improving walking ability in patients with ambulatory deficits due to MS.

Method
The trial was a multicenter, double-blind, placebo-controlled study that randomized patients ages 18 to 70 years in a 3:1 ratio to receive 14 weeks of treatment with either 10 mg of dalfampridine twice daily or placebo. Participants were permitted to remain on a stable regimen of their current medications, including immunomodulators, such as interferons.

One week after screening, patients began a 2-week placebo run-in before beginning 14 weeks of treatment with dalfampridine or placebo. Examinations began 2 weeks after initiation of the active treatment phase and then took place every 4 weeks. After 14 weeks patients discontinued treatment for 4 weeks, during which time they returned for examinations at 2-week intervals.

At each examination patients performed the timed 25-foot walk (T25FW) test twice with a maximum of 5 minutes of rest between tests. Patients could use assistive devices for the walking test if used consistently in all visits, and at each visit the average value of the two T25FW tests was used for analysis.

Population
The study was open to people with all types of MS, including primary-progressive, secondary-progressive, relapsing-remitting, and progressive-relapsing. The trial included 301 participants at 33 MS centers in the United States and Canada. There were 229 patients in the dalfampridine group and 72 patients in the placebo group.

For enrollment in the trial, patients were required to have the ability to complete 2 trials of T25FW in an average time of 8 to 45 seconds at the time of screening.

Patients were excluded from the study if they had an exacerbation of their MS within 60 days of the trial, evidence of epilepsy or seizures, or other conditions or medications that could interfere with the study.

The average age of patients in the trial was about 51 years, >90% were white, and males comprised 40% of the placebo group and 29% of the dalfampridine group.

Primary end point:
•    Change in walking speed measured by T25FW

Secondary end points:
•    Clinical significance of T25FW validated with 12-item multiple sclerosis walking scale (MSWS-12)
•    Ashworth score for spasticity
•    Lower extremity manual muscle test (LEMMT)

Results
A significantly greater proportion of people taking dalfampridine (35% vs 8%, P<.0001; odds ratio, 4.75; 95% confidence interval [CI], 2.08-10.86) were classified as timed walk responders, defined as subjects with an increase in walking speed in at least 3 of the 4 on-drug clinical visits compared to the best walking speed during 5 off-drug visits, as measured by the T25FW.

The average increase in walking speed over the 14-week treatment period compared to baseline for patients classified as timed walk responders was 0.51 feet/s (95% CI, 0.41-0.61) for the dalfampridine group and 0.10 feet/s (95% CI, 0.03-0.17) in the placebo group. These increases in speed represented improvements of 25.2% (95% CI, 21.5%-28.8%) for patients who received dalfampridine versus 4.7% (95% CI, 1.0%-8.4%) for patients who received placebo. This increase was maintained across the entire treatment period, and the increased response rate was seen across all 4 major types of MS.

For timed walk responders the average change in MSWS-12 scores was –6.84 (95% CI, –9.65 to –4.02) compared with 0.05 (–1.48 to 1.57) for nonresponders, independent of what treatment the patients received (P=.0002).

In addition, statistically significant increases in leg strength as measured by the LEMMT were seen in both the dalfampridine timed walk responders (P=.0002) and the dalfampridine timed walk nonresponders (P=.046) compared with placebo.

Adverse events that occurred in >5% of patients who received dalfampridine or placebo, respectively, included falls (16% vs 15%), urinary tract infection (14% vs 14%), dizziness (8% vs 6%), insomnia (8% vs 4%), fatigue (6% vs 3%), nausea (6% vs 4%), upper respiratory tract infection (6% vs 10%), asthenia (6% vs 6%), back pain (6% vs 0%), balance disorder (6% vs 3%), and headache (6% vs 6%).

Two serious adverse events that were judged potentially related to treatment with dalfampridine and led to discontinuation were anxiety in 1 subject and a focal seizure in another subject that was observed during an occurrence of sepsis associated with pneumonia.

Safety Notes
Ampyra, when given at doses greater than that recommended (10 mg twice a day), can cause seizures. The most common adverse reactions reported by patients taking Ampyra in clinical trials include urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling in the nose or throat, constipation, diarrhea, indigestion, throat pain, and burning, tingling, or itching of skin.

Ampyra should not be used in patients with moderate-to-severe kidney disease. In these patients, blood levels with the drug approach those associated with the occurrence of seizures. Ampyra is also contraindicated for patients with a history of seizures.

The FDA approved Ampyra with a Risk Evaluation and Mitigation Strategy program comprising a medication guide and communication plan. The goals of the communication plan are to inform patients about the serious risks, including seizures, associated with use of higher than recommended doses of Ampyra therapy, and the change of the established name from fampridine to dalfampridine.

Ampyra Facts
•    Dalfampridine was approved on January 22, 2010
•    Ampyra is marketed by Acorda Therapeutics
•    Ampyra will be manufactured by Elan Drug Technologies
•    More than 450 people are enrolled in extension trials