By Richard Robinson
An old drug is poised to offer life-saving treatment for a rare disease, based on a recent trial whose dramatic results experts are calling “quite convincing” and “a model” for therapy development. The disease is familial amyloid polyneuropathy (FAP), affecting an estimated 10,000 people worldwide. The drug is diflunisal, a once-common nonsteroidal anti-inflammatory agent no longer in widespread use. The trial, published in the Dec. 25 Journal of the American Medical Association, showed that, compared with placebo, long-term treatment with diflunisal significantly slowed worsening of both electrophysiologic and clinical indicators.
FAP is an autosomal dominant disease caused by a mutation in the gene for transthyretin, a thyroxine transporter made primarily in the liver. Transthyretin normally forms as a tetramer, with a central pocket that holds thyroxine, “and thyroxine, when it binds, increases the stability of the tetramer,” the lead investigator John Berk, MD, associate professor of medicine at Boston University Medical School and clinical director of the Center for Amyloidosis at Boston Medical Center, explained in an interview with Neurology Today.
Jeffery Kelly, PhD, a physical biochemist, began searching 15 years ago for chemical candidates whose shapes and binding properties mimic thyroxine. “The idea is simply to keep the tetramer together,” Dr. Berk said. Several candidates emerged, including diflunisal, which had the advantage of being a Food and Drug Administration-approved drug, with an established safety record and generic status. In recent years, the FDA has promoted the idea of just this kind of repurposing as an alternative route to drug development.
Dr. Berk organized the trial, which involved 130 patients at eight centers in the United States, Europe, and Japan. Patients received 250 mg diflunisal twice daily, or matching placebo, for two years. Eligible patients had biopsy-proven amyloid deposits, a positive gene test, and clinically detectable sensorimotor or autonomic neuropathy. Prior liver transplantation was an exclusion criterion. Most transthyretin is made in the liver, and transplantation is an important treatment mode for FAP patients.
The primary endpoint was the Neuropathy Impairment Score plus 7 nerve tests (NIS+7), which combines clinical assessment with a wide variety of measures of nerve integrity and function. The NIS+7 has been validated as a longitudinal outcome measure in diabetic neuropathy, a disorder similar to FAP in clinical and histological manifestations, though far less rapidly progressing. Dr. Berk noted that a 2-point change in the scale is considered clinically meaningful, and is the average change seen in diabetic neuropathy over 2.3 years.
Twenty-seven of the 64 patients randomized to receive diflunisal, and 40 of the 66 receiving placebo, dropped out during the study. Dr. Berk was not surprised by the high drop-out rate. “The change in neurologic function over time is permanent, so patients are playing for really high stakes” by enrolling in the trial, rather than finding a physician to prescribe the drug off-label on the hope that it was effective. Several patients who dropped out did just that. “We also strongly recommended that everyone entering the trial undergo a liver transplant evaluation, and be listed on the recipient list, so they maintained all their options.”
He noted that discontinuation due to disease progression was twice as common among patients receiving placebo. Nine deaths in the placebo group, and four in the diflunisal group, occurred during the two-year study, almost all after discontinuation.
Dr. Berk dealt with the high drop-out rate by using an intent-to-treat analysis, analyzing all enrolled patients in both groups on their final outcomes. On this basis, diflunisal-treated patients did far better than those receiving placebo, with NIS+7 scores increasing (worsening) by 8.2 points, versus 26.3 points for placebo (p<0.001). Functionally, that difference translates into maintaining the ability to rise from a chair or walk unaided.
“That diflunisal treatment so resoundingly met all the endpoints with dramatic statistical significance was just stunning to us,” Dr. Berk said. “We did not expect those results.” Benefits from treatment were seen regardless of type of mutation — more than 100 are known — degree of neuropathy at entry, or sex.
“We think it is a huge step forward for this lethal genetic disease. It makes available a treatment that is validated, and is now the alternative to a liver transplant.”
The study was supported by grants from the National Institute of Neurological Diseases and Stroke, the Orphan Products Division of the FDA, the Young Family Amyloid Research Fund, and the NIH National Center for Advancing Translational Sciences.
See an extended discussion of the study methodology from the author and outside experts in the Feb. 6 issue of Neurology Today. Browse our archives for more exciting research on polyneuropathies: http://bit.ly/1edv2s7.