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Acorda Therapeutic's MS Drug Ampyra Could Stumble

Acorda Therapeutics is feting the decision by the U.S. Food & Drug Administration (FDA) to approve the marketing of Ampyra (dalfampridine), the first (and only) oral treatment indicated to improve walking in patients with multiple sclerosis (MS). In approving Ampyra, however, have U.S. health regulators downplayed potential efficacy and safety issues due to political and unrelenting pressure from The National MS Society, the most powerful MS advocacy group (and which funded early-stage studies in the development of this drug)?

Ampyra, a sustained-release matrix tablet form of the investigational drug Fampridine SR, is designed to block specialized potassium (K+) channel leaks from axons and restore nerve impulses to damaged mylenin sheaths, the protective coating surrounding nerve fibers in the central nervous system. By reconnecting "nerve circuitry" it's been postulated that the drug could possibly restore some amount of motor and sensory function. Unfortunately initial clinical trials with chronic spinal cord injuries (CSI) failed to demonstrate any functional improvements (although recent trial data has been more encouraging in CSI).

MS patients also suffer damage to myelin sheaths, causing difficulty in walking, loss of balance, numbness, vision problems, and paralysis. Ignoring the failed CSI trials, Acorda Therapeutics (NASDQ: ACOR) turned its attention to usage of Fampridine SR in improving the walking ability in patients with multiple sclerosis. Controversial results from two late stage trials -- such as less than robust primary outcome data on the walking speed (as measured by the Timed 25-Foot Walk) of people taking twice-daily dose of Fampridine SR compared to people taking placebo -- formed the basis of information submitted in the company's New Drug Application (NDA).

Novelist Oscar Wild said: "One can give a really unbiased opinion only about things that do not interest one." No doubt The National MS Society and related support groups are committed to -- in what they view - -are the best treatment options for those suffering from degenerative neuromuscular diseases, but have best intentions blinded them to Ampyra's glaring limitations?

Central to the advisory panel's review of Ampyral was whether the improvements seen with the drug were truly significant to patients. Wishful desires aside, MS patients and their family members would be prudent to heed the words of the late Aaron Levenstein (Business Professor at Baruch College): "Statistics are like bikinis. What they reveal is suggestive, but what they conceal is vital." There are plenty of statistics revealed and concealed in the 177 pages of the Fampridine SR background information and clinical trial data given to the Peripheral and Central Nervous System Drugs Advisory Committee:

  • In clinical trials, over 35% of MS patients taking Ampyra were able to walk faster (the primary efficacy variable in both trials), said Andrew D. Goodman, MD, director of the multiple sclerosis center at the University of Rochester and the lead investigator in the clinical studies. Drilling down into the data, one uncovers that the walking speed change favored the Fampridine group by just 0.88 seconds (to complete the 25-foot walk) in the first study (MS-F203) and by a scant 0.5 - second difference in the second pivotal trial (MS-F204).
Improvements in walking speed can mean can "mean things like getting to the bathroom on time before having an accident, or getting across the street before the light changes," Goodman told WebMD. With all respect to Dr. Goodman, can someone tell me how one-half a second difference will be the critical variable in avoiding having an accident in one's pants?
If you want to inspire confidence, give plenty of statistics. It does not matter that they should be accurate, or even intelligible,as long as there is enough of them. ~ English author Lewis Carroll (1832 - 1898)
  • Among other under-reporting findings -- the walking speed at the end of the 14-week double-blind treatment phase (visit 6) was not clinically significant between the Fampridine and placebo groups, too. For example, in MS-F203 the visit 6 walking speed (ft/sec) was 2.16 for placebo-treated patients and 2.35 for Fampridine-treated patients (p=0.19).
  • In the 12-item Multiple Sclerosis Walking Scale (MSW-12), a self-rated measure of walking ability, timed walk-responders on Fampridine reported feeling less disabled in daily activities requiring mobility than than timed walkers on placebo. Unfortunately, a major limitation in trying to infer the practictal relevance of this improvement for patients is self-limiting: the MSW-12 assesses function based on the timed 25-foot walking test, and as both are already correlated, it wouldn't be unexpected to expect that patients doing better on the timed 25-foot walk also scored better on the MSW-12. Therefore, a posteriori, "it is not clear that this truly validates the significance of the responder analysis," said an FDA panel investigator (responder assessments changes were statistically insignificant, too).
Likewise, there are unaddressed concerns that the drug might afford nothing more than short-term relief from this often progressive and debilitating disease. In the 507 Fampridine-treated patients observed exclusively in MS trials, 33 patients (6.5%) had a reported MS relapse, compared with nine patients (3.8%) in placebo arms.

Although the risk of seizure reported with Fampridine is reported to be dose-related -- occuring more frequently with immediate release dosing -- the drug's narrow therapeutic index warrants that Ampyra-treated patients be closely monitored. Ampyra, when given at doses greater than that recommended (10 milligrams twice a day), can cause seizures, with a doubling of the dosage (intended to be marketing) reportedly increasing seizure risk ten-fold, according to published data on file with the FDA.

In addition, FDA investigators observed that in MS controlled trials, 84.8 percent of patients receiving Fampridine 10 mg twice daily reported one or more adverse events, with (suspected) urinary tract infections (14.5%), insomnia (9.3%), and dizziness (7.8%) the most common events. MS and SCI subjects experiencing one or more adverse events leading to discontinuation totaled 14.6 percent in Fampridine-treated patients.

No doubt Ampyra will prove to be of clinical utility to some MS patients. However, with only modest efficacy data and an uncertain safety profile, justifying an annual price tag of $10,000 (or more) to insurers and altering the prescribing habits of neurologists will require more than the goodwill of the MS lobby.

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