Onpattro (Patisiran)

Onpattro (patisiran) is a treatment for familial amyloid polyneuropathy (FAP) by Alnylam Pharmaceuticals. It is approved in the U.S., Europe, Japan, Canada, Switzerland, and Brazil to treat adult patients.

How does Onpattro work?

Onpattro uses a technology that researchers call RNA interference or RNAi. Molecules known as small interfering RNAs, or siRNAs, regulate gene expression or how much protein cells will make from a particular gene. By harnessing this pathway, scientists can design therapies that selectively target mutated genes and turn off the production of faulty proteins.

FAP, an inherited disease, is caused by mutations in the TTR gene. These mutations 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. Abnormal transthyretin can lead to deposits of amyloid fibrils — or protein clusters — inside nerve cells, and in the heart and gastrointestinal tract, causing the symptoms of this disease.

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

Onpattro in clinical trials

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

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

A Phase 2 extension (NCT01961921) of this trial evaluated the safety of Onpattro, injected Onpattro every three weeks for two years, in 27 FAP patients. Treatment was found to lead to 80% reductions in the level of faulty transthyretin, a drop sustained for more than 24 months. The results also indicated that Onpattro improved patients’ neurological symptoms. Six patients experienced serious adverse events, but all were determined to be unrelated to the treatment. 

A Phase 3 trial (NCT01960348) evaluated the safety and effectiveness of Onpattro in 200 adults with FAP. Researchers randomly assigned patients to either 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 lowered levels of the abnormal transthyretin protein and improved FAP-related symptoms. Patients treated with Onpattro also reported improvement in their quality of life compared with those given a placebo. The most common adverse effects of Onpattro treatment were upper respiratory tract infections and infusion-related reactions.

Other information

Patients using Onpattro as therapy will need to take a daily vitamin A supplement. This is because the medication reduces levels of vitamin A in the blood.

The U.S. Food and Drug Administration designated Onpattro an orphan drug in June 2012 and placed it on fast track development in November 2013. The agency approved Onpattro to treat adults with FAP in August 2018.


Last updated: July 16, 2020


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