ARTICLE IN BRIEF
Investigators reported that diflunisal, a once-common nonsteroidal anti-inflammatory agent no longer in widespread use, significantly slowed worsening of both electrophysiologic and clinical indicators in patients with familial amyloid polyneuropathy.
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.
But the significance of the trial goes even beyond the emergence of an important treatment for patients with FAP. The choice of diflunisal arose from a detailed understanding of the molecular consequences of the mutation that causes the disease. Its success makes clear the potential of drug design based on that level of understanding, and is likely to spur the search for other neurologic diseases for which such intimate molecular knowledge can lead to finely tailored therapy.
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.
However, most thyroxine is transported by another protein, leaving much of the transthyretin empty most of the time, and largely unnecessary for health. Mutations further destabilize the empty tetramer, freeing monomeric transthyretin. Free transthyretin has a propensity to misfold and form amyloid deposits throughout the body, including in peripheral nerves and the heart.
With all that in mind, 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. “So it's a big deal,” Dr. Berk said.
The effect on reducing disease progression was also seen in secondary outcome measures, including stabilization of quality of life and slower decline of body mass index. The proportion of patients whose decline was essentially halted by treatment was 30 percent in the diflunisal group, and 9 percent in the placebo group. “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 the results of the trial are clearly striking,” he continued. “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.” He noted that a recent trial of another transthyretin stabilizer, called tafamidis, did not meet its primary endpoint. The European Commission gave it provisional approval, but the FDA has required more studies.
Because diflunisal is already available, it is likely to quickly become the standard treatment for FAP, at least until gene silencing of transthyretin advances. A recent study showed the ability of interfering RNA to lower transthyretin levels in FAP patients. Longer-term dosing and functional benefits still need to be tested. Diflunisal is also likely to offer patients a way to delay, or perhaps avoid, a liver transplant, which ameliorates, but does not cure, the disease.
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.
“I think the results are quite convincing,” said Colin Chalk, MD, associate professor of neurology and neurosurgery at McGill University in Montreal. “The study was rigorously done, using measures most of us in the peripheral nerve community would consider gold standards to measure progression of peripheral nerve disease.” An important unanswered question, he noted, was whether diflunisal can improve cardiac function. “Although neuropathy is a very important part of the morbidity of this disorder, what kills patients is the cardiac disease.”
Michael Shy, MD, professor of neurology at the University of Iowa in Iowa City, called the results “very exciting.” The molecular specificity of diflunisal means it is not an appropriate therapy for the many other genetic neuropathies, “but it is a model for how using this type of approach can lead to a rational treatment, which can be taken to patients to see if it shows an effect.”
Dr. Berk encourages neurologists to consider FAP in patients with undiagnosed peripheral neuropathy. “Relying on a positive family history is probably not a good strategy,” he said, since the manifestations may be subtle or completely missed.
Dr. Chalk agreed. “I think this study will encourage people to look more carefully for this disease in their clinics, in patients with undiagnosed neuropathy. You don't want to overlook a potentially treatable disease.”