Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial

By J. Berk, O. Suhr, L. Obici, Y. Sekijima, S. Zeldenrust, T. Yamashita, M. Heneghan, P. Gorevic, W. Litchy, Janice F. Wiesman and 15 more. Journal of the American Medical Association (JAMA), 2013

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Importance Familial amyloid polyneuropathy (ATTR-FAP), a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a non-steroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. Objective To determine the effect of diflunisal on polyneuropathy progression in patients with ATTR-FAP. Design, Setting, and Patients We conducted an investigator-initiated international, randomized, double-blind, placebo-controlled study at amyloid centers in Sweden (Umea), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, New York, Rochester, MN) from 2006 through 2012. 130 ATTRFAP patients with clinically detectable peripheral or autonomic neuropathy were randomly assigned to diflunisal 250 mg or placebo twice daily for 2 years. Main Outcome Measures The primary endpoint, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurologic deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality of life questionnaire (Short Form-36 (SF-36)) and modified body mass index (mBMI). Results One hundred thirty randomized patients (66 placebo, 64 diflunisal) underwent serial NIS+7 evaluations over 2 years. Due to attrition, we employed likelihood based modeling and multiple imputation (MI) analysis of baseline to 2 year data. By MI, NIS+7 increased 25.0 points (95% CI, 18.4 to 31.6) among placebo and 8.7 points (95% CI, 3.3 to 14.1) in the diflunisal group, a difference of 16.3 points (95% CI, 8.1 to 24.5, p=0.001). Mean SF-36 physical scores fell 4.9 points (95% CI, −7.6 to −2.2) among placebo and rose 1.5 points (95% CI, −0.8 to 3.7) in the diflunisal group (p=0.003). SF-36 mental scores declined 1.1 (95% CI, −4.3 to 2.0) among placebo while increasing 3.7 (95% CI, 1.0 to 6.4) in the diflunisal group (p=0.022). By responder analysis, 29.7% of diflunisal and 9.4% of placebo exhibited neurologic stability at 2 years (< 2 points NIS+7 increase) (p=0.007). Conclusions and Relevance Among patients with ATTR-FAP, the use of diflunisal compared with placebo for 2 years reduced the rate of progression in neurologic impairment and preserved quality of life. Although longer term follow up studies are needed, these findings suggest benefit of this treatment for ATTR-FAP.

Subfields: Cell Biology, Molecular Biology, Physiology

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