Onpattro (patisiran) is a therapy developed by Alnylam Pharmaceuticals and approved by the U.S. Food and Drug Administration to treat familial amyloid polyneuropathy (FAP).

How Onpattro works

Onpattro uses a technology known as RNA interference, or RNAi. Gene expression, or how much protein will be made from a particular gene is regulated by molecules called small interfering RNAs, or siRNA. By harnessing this pathway, scientists can design RNA therapies that selectively target mutated genes and turn off the production of faulty proteins.

FAP, also known as hereditary ATTR amyloidosis, is an inherited disease caused by mutations in the TTR gene that lead to the production of misfolded transthyretin, a protein produced mainly in the liver.

Transthyretin normally transports vitamin A and the thyroid hormone thyroxine in the blood and cerebrospinal fluid, or fluid around the brain and spinal cord. Abnormal transthyretin can lead to deposits of amyloid fibrils — or protein clusters — in the nerves, heart, and gastrointestinal tract, causing the symptoms of FAP.

Onpattro consists of lipid nanoparticles that contain siRNA. The nanoparticles deliver the siRNA to liver cells, where they significantly reduce TTR gene expression.

Onpattro in clinical trials

Alnylam conducted a Phase 1 clinical trial (NCT01559077) to evaluate the safety, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of Onpattro in 32 FAP patients and 17 healthy volunteers at several dose levels. The results, published in the New England Journal of Medicine, showed that Onpattro generated a rapid, dose-dependent, and durable reduction in abnormal transthyretin protein production.

A Phase 2 clinical trial (NCT01617967) was conducted to determine the safety, pharmacokinetics, and pharmacodynamics of multiple doses of Onpattro in 29 FAP patients. The results showed that Onpattro reduced the levels of abnormal transthyretin protein by more than 80%. These results were published in the Orphanet Journal of Rare Diseases.

A Phase 2 extension study (NCT01961921) of this trial was conducted to evaluate the safety of injected Onpattro every three weeks for two years in FAP patients. Twenty-seven patients were enrolled in the study. Onpattro treatment led to 80% reductions in levels of faulty transthyretin — an outcome that was sustained for more than 24 months. The results also indicated that Patisiran improved patients’ neurological symptoms. Six patients experienced serious adverse events but these were unrelated to the treatment. 

A Phase 3 trial (NCT01960348) evaluated the safety and effectiveness of Onpattro treatment in 200 adults with FAP. Patients were randomly assigned to either receive a placebo (77 patients) or Onpattro (148 patients) once every three weeks for 18 months. The results, published in the New England Journal of Medicine, showed that Onpattro reduced the levels of abnormal transthyretin protein and improved FAP-related symptoms. Patients receiving Onpattro also reported improvement in their quality of life compared with placebo groups. The most common adverse effects reported with Onpattro treatment were upper respiratory tract infections and infusion-related reactions.

Other information

Patients receiving Onpattro therapy will need to take a daily vitamin A supplement, as Onpattro reduces levels of vitamin A in the blood.

The FDA granted Onpattro orphan drug designation in June 2012 and fast-track designation in November 2013. Onpattro was approved by the FDA to treat FAP in August 2018.

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