Treatment with the nonsteroidal anti-inflammatory drug (NSAID) diflunisal for 2 years in patients with hereditary transthyretin-type familial amyloid polyneuropathy (ATTR-FAP) reduces the rate of progression of neurological impairment and preserves quality of life compared with placebo, a new study has determined.
ATTR-FAP is a genetic disease caused by aggregation of variant transthyretin. Untreated, patients with this disorder develop progressive neurological deficits, dying 10 to 15 years after disease presentation. The standard treatment is a liver transplant, but transplants are costly, organs are sometimes unavailable, and this option is not offered to older patients and those with advanced disease.
The new double-blind study is "pivotal," according to the authors, led by John L. Berk, MD, from the Amyloidosis Center, Departments of Medicine and Neurology, Boston University School of Medicine, Massachusetts. Not only does it demonstrate that diflunisal inhibits progression of polyneuropathy in patients with ATTR-FAP, using several measures, but it is the first randomized clinical trial involving a broad cross-section of the spectrum of disease and the most prevalent genotypes for ATTR, the authors write.
The study was published in the December 25 issue of JAMA.
Old Drugs Repurposed
A National Institutes of Health mission is to repurpose old drugs. Diflunisal is a generic agent that had lost its clinical relevance, but a previous phase 1 study showed that at a dose of 250 mg twice daily, the drug kinetically stabilizes circulating TTR tetramers, inhibiting release of the TTR monomer required for amyloidogenesis.
This new study enrolled 130 patients with ATTR-FAP from 8 centers in England, Italy, Japan, Sweden, and the United States. The participants were randomly assigned to receive either 250 mg of diflunisal twice daily or placebo.
The primary study endpoint was the Neuropathy Impairment Score plus 7 nerve tests (NIS+7), a composite scale that assesses, in part, muscle weakness, sensory loss, and decreased muscle stretch reflexes. A 2-point change in NIS+7 score identifies a minimal clinically detectable change in polyneuropathy progression.
At the end of 2 years, patients taking diflunisal exhibited significantly less progression of polyneuropathy than those taking placebo. The change in NIS+7 score from baseline was 26.3 points (95% confidence interval [CI], 20.2 - 32.4 points) in the placebo group and 8.2 points (95% CI, 2.9 - 13.6 points) in the diflunisal group, a between-group difference of 18.0 points (95% CI, 9.9 - 26.2 points; P ˂ .001)
Attrition was a prominent feature of the study and occurred unequally across treatment groups (40 patients from the placebo group and 27 from the treatment group discontinued the study). Disease progression was the predominant cause for dropping out of the study.
To address the uneven attrition issue, the researchers performed several sensitivity analyses, including last observation carried forward, "worse-case scenario," and dichotomous responder analyses. Multiple imputation analysis estimated a difference in change between the placebo and diflunisal groups of 16.3 points (95% CI, 8.1 - 24.5 points; P ˂ .001). Such a difference, said the authors, signals a clinically meaningful diflunisal effect.
"Confining neurological deficits to lower limb muscle function, a 16-point NIS+7 difference might represent a 50% decline of knee extensor and flexor strength plus ankle dorsiflexion in the placebo group with no change occurring in the treatment group, approximating the ability to rise from a chair or walk unaided."
The magnitude of polyneuropathy progression measured by the NIS+7 in the placebo group (25 points) far exceeded the progression reported in patients with diabetes (1.70 points) found in a previous study, "quantifying the devastating nature of ATTR-FAP," the authors write.
The findings extended across TTR mutations, sex, neuropathy severity, and major study sites. The results suggest that the diflunisal effect may extend to patients with advanced polyneuropathy, a population often deemed ineligible for orthotopic liver transplantations, said the authors.
Importantly, the drug affected not only the progression of neuropathy but also the quality of life for patients with FAP, "a critical element when considering the effect of new treatments," they write.
Diflunisal was well-tolerated. Gastrointestinal, renal, cardiac, and blood-related adverse events occurred in similar numbers by treatment group. Adverse events in the musculoskeletal and general disorders categories occurred more frequently in the diflunisal group, but drug-related adverse events did not differ between groups. There were no differences in serious adverse events.
The study is important in part because it provides invaluable natural history data on the rate of neurological disease progression in an inclusive and heterogeneous ATTR-FAP population that will be the foundation of future trials designs, said the authors.
The study was supported by grants from the National Institute of Neurological Diseases and Stroke, the Orphan Products Division of the US Food and Drug Administration, the Young Family Amyloid Research Fund, and the National Center for Advancing Translational Sciences, National Institutes of Health. Merck Sharp and Dohme Inc supplied study drug. Dr. Berk and 4 coauthors have received honoraria from Alnylam, ISIS, and Pfizer Pharmaceuticals. One coauthor has received support from Pfizer for activities as chairman of the Transthyretin Amyloidosis Outcome Survey, ISIS, and Alnylam Pharmaceuticals. One coauthor has received honoraria from Pfizer. One coauthor reports financial holdings in FoldRx Pharmaceuticals Inc. The other authors have disclosed no relevant financial relationships.
JAMA. 2013;30:2658-2667. Abstract
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Cite this: NSAID Halts Progression in Familial Amyloid Polyneuropathy - Medscape - Dec 30, 2013.