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New Targeted RNA-based Infusion to Treat Rare Polyneuropathy in Adults

First in a New Class of siRNA Therapeutics

The FDA has approved Onpattro (patisiran, Alnylam Pharmaceuticals) infusion for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults.  This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart, and other organs. It is also the first FDA approval in a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.

This new class of drugs, called siRNAs, works by silencing a portion of RNA involved in causing the disease. More specifically, Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.

Affecting about 50,000 people worldwide, hATTR is characterized by the buildup of amyloid in the body's organs and tissues, interfering with their normal functioning. These protein deposits most frequently occur in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands, and feet. Amyloid deposits can also affect the functioning of the heart, kidneys, eyes and gastrointestinal tract. Previous treatment options have focused on symptom management.

Onpattro is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.

The efficacy of Onpattro was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation, reflexes and autonomic symptoms compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.

The most common adverse reactions reported by patients treated with Onpattro are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea, and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision, and vitreous floaters. Onpattro leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.

The FDA granted this application fast track, priority review, breakthrough therapy, and orphan drug designations.

Source: FDA.gov, August 10, 2018

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