RNA Therapeutic Patisiran Improves Neurologic Impairment in hATTR Amyloidosis Patients


If approved, the therapeutic will be the first in a new class of medicines.

Alnylam Pharmaceuticals has announced the publication of a study on its new pivotal phase 3 clinical trial of a RNAi therapeutic for the treatment of hereditary ATTR (hATTR) amyloidosis, a highly rare and hereditary condition.

An estimated 50,000 individuals worldwide have hATTR amyloidosis, an inherited and progressive disease that prevents the transthyretin (TTR) protein produced in the liver from performing its normal function. The transport protein occurs in blood plasma and cerebrospinal fluid, serving as a major retinol binding protein and transporting circulating thyroxine. In patients with hATTR amyloidosis, mutations in the TTR gene cause abnormal amyloid proteins to build up in the body, causing damage to organs and tissue such as the heart and peripheral nerves. As a result, patients can experience a variety of symptoms, including numbness or tingling of the feet leading to significant disability, diarrhea, hypotension, erectile dysfunction, and cardiomyopathy (heart disease), which can all lead to a shortened lifespan.

A new study published on July 5, 2018, in the New England Journal of Medicine details the results of the APOLLO phase 3 clinical trial for patisiran, an investigational therapeutic for hATTR amyloidosis using RNA interference (RNAi). Patisiran works by targeting TTR in development and silencing production of disease-causing proteins, blocking the protein before it is made. By clearing and reducing deposition of amyloid proteins in tissues, patisiran may help restore function to tissues. The 18-month randomized, double-blind, placebo-controlled, global study included 225 enrolled patients from 19 countries with 39 genotypes. Patients were randomized at a 2 to 1 ratio for patisiran and placebo, respectively. Those receiving patisiran were administered at 0.3 mg/kg intravenously once every 3 weeks for 18 months. The study’s primary endpoint was the change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) relative to placebo.

Patients receiving patisiran saw improved measures of polyneuropathy, quality of life, daily activity, ambulation, nutritional status, and autonomic symptoms relative to patients receiving placebo. “This is the most severe hereditary neuropathy in the world,” said the trial’s principle investigator and the study’s lead author, David Adams MD, PhD, department of Neurology, coordinator of the National Reference Center for Familial Amyloid Polyneuropathy (FAP) and rare neuropathies, Bicêtre Hospital, Greater Paris University Hospitals, AP-HP, in an interview with Rare Disease Report®. Listing the numerous debilitating effects of the disease and lack of treatment options, Dr Adams’ explains that while hATTR amyloidosis is very rare compared with other conditions such as Parkinson’s disease, finding a solution for it became imperative.

“The positive impact on both neurologic impairment and quality of life in patients treated with patisiran was in marked contrast to the disease progression seen in placebo-treated patients in just 18 months,” said Dr Adams in a recent statement. “In fact, we observed improvement in neuropathy manifestations and quality of life in a majority of patisiran-treated patients, with some patients showing evidence of halting or reversal of disease progression during the study, including a transition from assisted to unassisted walking. The broad, international patient population recruited to APOLLO is characteristic of the wide disease spectrum seen in clinical practice, supporting the relevance of the potential beneficial effects of patisiran for patients worldwide afflicted with this progressive and generally fatal disease.”

Following completion of the APOLLO phase 3 study, all patients were eligible to screen for the Global OLE study, giving them an opportunity to receive patisiran on an ongoing basis.

There are currently no medicines approved by the US Food and Drug Administration (FDA) for hATTR amyloidosis, and patients have worked with specialists to manage symptoms, with liver transplantation as an option for some. Patisiran is now under Priority Review as a Breakthrough Therapy with the FDA, with an action date of August 11, and under accelerated assessment by the European Medicines Agency (EMA). If approved, patisiran will be the first in a new class of medicines.

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