Resumen de Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial
John L. Berk, Ole B. Suhr, Laura Obici, Yoshiki Sekijima, Steven R. Zeldenrust, Taro Yamashita, Michael A. Heneghan, Peter D. Gorevic, William J. Litchy, Janice F. Wiesman, Erik Nordh, Manuel Corato, Alessandro Lozza, Andrea Cortese, Jessica Robinson-Papp, Theodore Colton, Denis V. Rybin, Alice B. Bisbee, Yukio Ando, Shu-ichi Ikeda, David C. Seldin, Giampaolo Merlini, Martha Skinner, Jeffery W. Kelly, Peter J., Dyck
Importance Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal 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 familial amyloid polyneuropathy.
Design, Setting, and Participants International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012.
Intervention Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years.
Main Outcomes and Measures The primary end point, 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 neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data.
Results By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P?
Conclusions and Relevance Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.
Trial Registration clinicaltrials.gov Identifier: NCT00294671 Hereditary transthyretin amyloidosis (ATTR) is a lethal, autosomal dominant genetic disease caused by the aggregation of variant and wild-type transthyretin (TTR), a thyroxine transport protein predominantly produced by the liver.1,2 More than 100 different mutations in the TTR gene destabilize its tetrameric structure, promoting TTR dissociation and misassembly into oligomeric aggregates including amyloid fibrils.3,4 The process of TTR amyloidogenesis produces a spectrum of debilitating disease ranging from pure polyneuropathy (transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) to selective heart involvement.5,6 In ATTR-FAP, small- and large-fiber injury induce sensory and autonomic deficits accompanied by motor weakness in a length-dependent fashion, mimicking manifestations of diabetic polyneuropathy. Untreated, patients exhibit progressive neurological deficits, dying 10 to 15 years after disease presentation.7 Fewer than 10?000 people are estimated to be clinically affected worldwide.8 Orthotopic liver transplantation, standard treatment for FAP since its initial use in 1990, eliminates 95% of variant TTR from the blood and affects the course of disease.9,10 However, limited organ availability, exclusion of older patients and those with advanced disease, the high costs of transplantation, the risks of lifelong immunosuppression, and reports of disease progression following liver transplantation11,12 warrant development of alternative treatments.
Dissociation of TTR tetramers is the rate-limiting step of amyloidogenesis in patients with ATTR-FAP.13,14 Slowing TTR tetramer dissociation�either by interallelic trans suppression,13,15 in which a second TTR gene mutation counters the destabilizing effect of the first TTR mutation, or by the binding of small molecule kinetic stabilizers to TTR tetramers�appears to minimize clinical disease expression.16- 18 A phase 1 study demonstrated that diflunisal, a generic nonsteroidal anti-inflammatory drug, at a dosage of 250 mg twice daily successfully complexes to the thyroxine binding site and kinetically stabilizes circulating TTR tetramers, inhibiting release of the TTR monomer required for amyloidogenesis.16,19 Pursuing the National Institutes of Health (NIH) mission to repurpose old drugs, we conducted an investigator-initiated, international, multicenter, randomized, double-blind, placebo-controlled study to determine the effect of diflunisal on polyneuropathy progression in patients with ATTR-FAP.
