New therapies in hereditary amyloid neuropathies

Hereditary ATTR amyloidosis is a progressive and fatal disorder caused by variant transthyretin (TTR) deposition as amyloid. A progressive axonal neuropathy with autonomic involvement is a common presentation associated with variable heart involvement. Liver transplant was the first treatment available, but its benefits were limited. In the last decade three drugs were approved for the treatment of ATTR amyloidosis with polyneuropathy. Tafamidis is a TTR stabilizer presented as a 20 mg capsule for daily oral intake. The best treatment results are seen in female patients with early disease. No safety issues were detected. Patisiran is an interference RNA preventing the synthesis of wild and variant TTR in the liver. A dose of 300 μg/Kg is infused every three weeks after pre-medication with a low dose steroid. The phase 3 clinical trial showed a highly significant difference between treatment arms, with some degree of improvement in a large percentage of patients. Some mild infusion reactions may occur, but they are easily controlled. Inotersen is an antisense oligonucleotide that also prevents TTR synthesis. It is formulated for weekly subcutaneous injection. The pilot trial showed a highly statistically significant difference between treatment arms. The drug may cause severe thrombocytopenia and renal disease. Monitoring rules with frequent blood and urine analysis are needed. There are other drugs under development, addressing some unmet needs. Anyway, the approval of these three new drugs is changing a devastating and life-threatening disease into a chronic condition with better quality of life and prolonged survival.