Patisiran represents a significant advancement in medical treatment. Its approval by the U.S. Food and Drug Administration (FDA) was a substantial milestone, introducing an innovative therapeutic approach to a challenging condition. This highlights the potential of targeted therapies to change patient outcomes.
Understanding Patisiran and Its Target Condition
Patisiran, marketed under the brand name Onpattro, is a medication designed to treat hereditary transthyretin-mediated (hATTR) amyloidosis. This rare and severe genetic disorder is caused by a mutation in the transthyretin (TTR) gene. The TTR gene provides instructions for making the transthyretin protein. In individuals with hATTR amyloidosis, the mutated TTR gene produces misfolded TTR proteins.
These abnormally shaped TTR proteins accumulate as amyloid fibrils, which are sticky, insoluble deposits that build up in various organs and tissues throughout the body. This progressive accumulation can damage multiple organ systems, including the peripheral nerves, heart, and gastrointestinal tract. Common symptoms often include numbness or tingling in the hands and feet, carpal tunnel syndrome, and issues like severe constipation, diarrhea, and nausea. Heart-related symptoms can involve shortness of breath, leg swelling, and irregular heart rhythms. The disease is progressive and can significantly impact quality of life and lifespan.
Key Details of the FDA Approval
The FDA approved Patisiran on August 10, 2018, for the treatment of polyneuropathy in adults with hereditary transthyretin-mediated amyloidosis. This approval was noteworthy as Patisiran became the first RNA interference (RNAi) therapeutic sanctioned by the FDA. This new class of drugs represents a significant scientific breakthrough, leveraging a natural biological process to address disease at its genetic source.
The decision to approve Patisiran was supported by robust evidence from the APOLLO Phase 3 clinical trial, a randomized, double-blind, placebo-controlled study. This trial involved 225 patients with hATTR amyloidosis with polyneuropathy. The results demonstrated that Patisiran significantly improved neurological function and neuropathy-related quality of life compared to placebo over an 18-month period. Patients receiving Patisiran experienced stable or improved neuropathy, while those on placebo generally saw their condition worsen.
How Patisiran Works
Patisiran functions as an RNA interference (RNAi) therapeutic. RNAi is a natural cellular process that regulates gene activity by silencing specific genes. Patisiran specifically targets the messenger RNA (mRNA) responsible for producing the transthyretin (TTR) protein.
Once administered, Patisiran travels to the liver, where the TTR protein is primarily made. Inside liver cells, Patisiran releases small interfering RNA (siRNA) molecules. These siRNA molecules are designed to be complementary to the TTR mRNA. When the siRNA binds to the TTR mRNA, it triggers the RNA-induced silencing complex (RISC) to cleave and degrade the TTR mRNA, essentially “turning off” the gene’s instruction to produce TTR protein. This process significantly reduces the production of both normal and misfolded TTR proteins, preventing the formation of amyloid deposits. Studies have shown that a single dose of Patisiran can reduce mean serum TTR levels by approximately 80% within 10 to 14 days, with sustained reductions with continued dosing every three weeks.
Impact of the Approval on Patients
The FDA approval of Patisiran had a profound impact on individuals living with hATTR amyloidosis. Before Patisiran, treatment options for this rare and progressive genetic disorder were limited, often involving liver transplants or off-label use of other medications. Patisiran introduced the first targeted therapy to address the underlying cause of polyneuropathy in hATTR amyloidosis.
This new treatment offered a significant improvement in patients’ quality of life and functional capacity, as demonstrated in the APOLLO trial. Patients treated with Patisiran showed improvements in daily activities, ambulation, and nutritional status, which typically decline rapidly in this progressive disease. The ability of Patisiran to slow or even reverse disease progression provided new hope for patients and their families. This approval also paved the way for other RNAi-based therapies, establishing a new class of medicines that can target diseases at their genetic origin.