New Drug News: Regulatory Approval Brings siRNA into the Rare Disease Toolbox

Onpattro™ Secures FDA Approval

In August 2018, the U.S. Food and Drug Administration approved Onpattro™ (patisiran) infusion for the treatment of stage 1 or stage 2 polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults.1 This approval broke new ground on two different levels: it is the first approved treatment for peripheral nerve disease caused by hATTR and the first drug in the class of small interfering ribonucleic acid (siRNA) to receive FDA approval. The FDA approval was followed in September by a marketing authorization from the European Medicines Agency; an NDA marketing application has since been submitted in Japan.2,3

Hereditary ATTR Amyloidosis

Hereditary ATTR amyloidosis is a rare autosomal dominant condition associated with over 120 different mutations in the transthyretin gene (TTR) and affects about 50,000 people worldwide. TTR is a transport protein that carries the thyroid hormone thyroxine and retinol in blood serum and cerebrospinal fluid. The gene mutations in TTR that cause hATTR amyloidosis generate abnormal, misfolded TTR proteins in the liver that cluster together and accumulate as amyloid fibers and, ultimately, deposits in diverse tissues and organs that disrupt normal functioning.

The pathological amyloid deposits commonly affect the peripheral nervous system, resulting in nerve damage — polyneuropathy — causing symptoms that range from loss of sensation to pain and ultimately immobility in the extremities. TTR-associated amyloid deposits in other organ systems can cause autonomic dysfunction, cardiomyopathy, glaucoma and other ocular disorders, kidney dysfunction and progressive dementia.

As is the case for many rare diseases, treatment for patients with hATTR amyloidosis has focused on the management of the specific symptoms that present in an individual patient. Until now, the only treatment that addressed the cause of the disease itself was liver transplantation, but that is only suitable for a subset of patients.

Silencing via siRNA

In contrast, as a first-in-class siRNA drug, Onpattro presents a unique mechanism of action that reduces the production of the aberrant TTR protein that drives hATTR amyloidosis, thereby treating the root cause of the disease. siRNA comprises a class of natural double-stranded RNA molecules that were first discovered by geneticist David Baulcombe’s group in plants in 1999.4

Since then, siRNAs have been shown to operate in post-transcriptional gene silencing as part of a broader endogenous mechanism called RNA interference (RNAi). RNAi occurs when an siRNA separates into single-stranded RNA molecules that bind to the mRNA of an individual gene via complementary base pairing. This hybrid RNA recruits the RNA-induced silencing complex (RISC), which digests the mRNA, preventing translation into a protein.

At the time of its discovery, RNAi represented a novel paradigm of cellular control of gene expression, since control was believed to occur before transcription (e.g., transcription inhibitors, gene silencing and chromatin modification) or after translation (e.g., targeting proteins for degradation). RNAi plays a role in cellular immunity against viruses, transposons and other foreign genetic material and in downregulation of endogenous genes, particularly for morphogenetic timing and the maintenance of stem cells in an undifferentiated state.

In the intervening decades, siRNAs have been widely used in the laboratory to study the effects of knocking down a gene product, particularly in model systems (e.g., Caenorhabditis elegans and mammalian cells) that are not tractable for conventional gene disruption, as well as to assess the role of essential genes. However, until now, they have not been used for the treatment of disease in humans. 

With the approval of Onpattro™, siRNA joins the new generation of nucleic acid–based drug classes — gene therapy, oligonucleotides exon-skipping drugs — in development or entering the marketplace for the treatment of rare diseases that address the causes rather than the symptoms of these conditions.

Promising New Drug Classes

With the approval of Onpattro™, siRNA joins the new generation of nucleic acid–based drug classes — gene therapy, oligonucleotides and exon-skipping drugs — in development or entering the marketplace for the treatment of rare diseases that address the causes rather than the symptoms of these conditions. As FDA Commissioner Scott Gottlieb noted, “This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms. New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses.”1

Onpattro™ comprises patisiran — an si-RNA targeting TTR mRNA — encapsulated in a lipid nanoparticle to ensure delivery of the drug to the liver via infusion, where it disrupts production of abnormal TTR protein, reducing the formation of amyloid fibrils and deposits. Its efficacy was demonstrated in a global phase III clinical trial (APOLLO) of 225 patients, in which patients in the treatment arm showed better outcomes on measures of polyneuropathy — including autonomic symptoms, pain, sensation and muscle strength — than those who received placebo infusions (modification in the Neuropathy Impairment Score +7 over baseline at 18 months).

Approval of Onpattro™ leveraged multiple FDA processes designed to expedite development and review of drugs targeting serious conditions that fill unmet medical needs, receiving Fast Track, Priority Review, Breakthrough Therapy and Orphan Drug designations owing to its novel mechanism and the rarity of the targeted disease. 

Onpattro™ was developed and is marketed by Alnylam Pharmaceuticals, a U.S. biopharmaceutical company focused on the development of RNAi-based therapeutics. The company has a pipeline of products vying to follow the path blazed by Onpattro™ that target rare conditions, including acute hepatic porphyrias (givosiran), hemophilia (fitusiran) and homozygous familial hypercholesterolemia (inclisiran).


  1. FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease. U.S. FDA. 10 Aug. 2018. Web.
  2. Alnylam Receives Approval of ONPATTRO™ (patisiran) in Europe. Alnylam Pharmaceuticals. 30 Aug. 2018. Web.
  3. Alnylam Announces Submission of New Drug Application in Japan for ONPATTRO™ (patisiran sodium) for Treatment of Hereditary ATTR Amyloidosis. Alnylam Pharmaceuticals. 16 Sep. 2018. Web.
  4. Hamilton, Andrew J., David C. Baulcombe. “A species of small antisense RNA in posttranscriptional gene silencing in plants.” Science. 286: 950–952 (1999).

David Alvaro, Ph.D.

David is Scientific Editorial Director for That’s Nice and the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University and a Ph.D. in Genetics and Development from Columbia University.