PracticeUpdate Neurology Best of 2018

TOP STORIES 2018 6

Neuromuscular Diseases: Hereditary Transthyretin Amyloidosis By Marinos C. Dalakas MD H ereditary transthyretin (TTR) amyloid neuropathy is the first disease where oligonucleotide drugs, administered systemically, can improve symptoms or arrest disease progression.

inhibits the production of TTR by the liver, 1 and an RNA interference therapeutic called patisiran, which inhibits the hepatic synthesis of TTR, 2 induce significant clinical benefits associated with a dose-de- pendent and sustained reduction of circulating TTR levels. Patisiran was used intravenously every 3 weeks in 225 patients, and inot- ersen was used subcutaneously in 172 patients once weekly for 64 weeks. Both drugs had a remarkable effect in suppressing the rate of neuropathy progression and significantly improved the main clini- cal manifestations, including autonomic symptoms, gait instability, and quality-of-lifemeasures. The serumconcentration of TTRwas reduced by 81% in the patisiran study and by 71% in the inotersen trial. Most importantly, over the 18-month therapy, 60%of the patients improved. These two independent large trials are remarkable because they convincingly show for the first time that oligonucleotide drugs admin- istered systemically can improve patients with hereditary amyloid peripheral neuropathy. The improvement or even reversal of the patients’ sensorimotor deficits and disabling autonomic symptoms is a breakthrough for such a devastating neuropathy that we could not previously treat. Both drugs have now gained FDA approval, the inotersen as Tegsedi and the patisiran as Onpattro. This is a his- toric approval, the first of its kind in human therapeutics, highlighting that drugs in the category of RNA interference or RNA targeting can help patients with a catastrophic hereditary disease. Although not yet tested, the results provide hope that these drugs may have the potential to prevent clinical manifestations in pre-symptomatic patients with mutations in the gene encoding TTR. References 1. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):22-31. 2. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21. www.practiceupdate.com/c/75966

Hereditary TTR amyloid neuropathy is a pro- gressive, autosomal-dominant polyneuropathy

that leads to severe disability and death. The disease is caused by mutations in the gene encoding TTR, a protein synthesized in the liver. TTR is normally a tetrameric protein complex, but, in patients with TTR polyneuropathy, the mutations in the TTR gene destabilize its tetrameric structure, resulting in toxic monomers that aggregate as misfolded amyloid fibrils, which accumulate in multi- ple organs including peripheral nerves, ganglia, skeletal muscle, and heart, leading to a progressive sensorimotor and autonomic polyneuropathy often associated with cardiomyopathy. The dis- ease is incurable, with an average life expectancy of 3 to 15 years from symptom onset. Liver transplantation has been the standard of care, but continued deposition of wild-type TTR amyloid after transplantation limits its effectiveness. It has been proposed that the disease can be treated and perhaps prevented by approaches that reduce the availability of themisfolded TTR monomer. Two recently published phase III controlled studies in patients with TTR amyloid neuropathy have now shown that two agents, amodified antisense oligonucleotide called inotersen, which " …they convincingly show for the first time that oligonucleotide drugs administered systemically can improve patients with hereditary amyloid peripheral neuropathy. "

T his year’s story of the year in the field of stroke was the paper reporting the results of the DEFUSE 3 trial, 1 a mul- ticenter, randomized, open-label trial, with blinded outcome assessment, of thrombec- tomy in patients 6 to 16 hours after they were last known well whose imaging revealed ischemic brain tissue that was not yet infarcted. Participants in this trial all had proximal middle cerebral artery occlusion or internal carotid artery occlusion, an ini- tial core infarct volume under 70 cc, and a volume of ischemic (hypoperfused) tis- sue on perfusion imaging that was at least 1.8 times larger than the core infarct. The 182 participants were randomly assigned to endovascular therapy (ET) or standard medical therapy alone. The primary out- come was the modified Rankin Scale score (a measure of functional disability) at 90 days post stroke. The results revealed a favorable shift in the distribution of func- tional outcomes on the primary outcome

Stroke: The DEFUSE 3 Trial By Argye Elizabeth Hillis MD, MA

measure (OR, 2.77; P < .001) in those who received ET versus those who received medical therapy alone. Furthermore, more patients in the ET group were functionally independent, with a modified Rankin score of 0 to 2 (45% vs 17%; P < .001). Mortality at 90 days was marginally lower in the ET group (14% vs 26%; P = .05), and there was group difference in the frequency of symp- tomatic intracranial hemorrhage or serious adverse events. This study was published only a few weeks after the DAWN trial 2 also revealed marked better functional outcomes in patients with small core infarct but disproportionate neurological deficit – indicating a larger volume of ischemic hypoperfusion tissue than core infarct – treated 6 to 24 hours of last seen normal if they received ET versus medical treatment alone. Together, these studies provide complementary evi- dence that a subgroup of stroke patients can strongly benefit from ET at least up to

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