2018: First siRNA Drug Approved (Patisiran) (2018)

The FDA approval of patisiran (Onpattro, Alnylam Pharmaceuticals) for hereditary transthyretin-
mediated amyloidosis (hATTR amyloidosis) with polyneuropathy in August 2018 marked the first
approval of an RNA interference (RNAi) therapeutic and validated a gene-silencing mechanism that
had been proposed as a drug modality for over two decades. RNAi, discovered by Andrew Fire and
Craig Mello in 1998 and recognised with the 2006 Nobel Prize, is a natural cellular pathway in
which small interfering RNAs (siRNAs) direct the RNA-induced silencing complex (RISC) to degrade
complementary messenger RNA sequences, preventing protein translation.

hATTR amyloidosis is caused by mutations in the transthyretin (TTR) gene; misfolded variant TTR
protein accumulates as amyloid fibrils in peripheral nerves and the heart, causing progressive
polyneuropathy and cardiomyopathy. The TTR gene is almost exclusively expressed in hepatocytes,
making the liver the natural delivery target. Patisiran delivers a 21-nucleotide siRNA duplex
targeting TTR mRNA encapsulated in a hepatocyte-targeted lipid nanoparticle (LNP), enabling
endosomal escape and cytoplasmic RISC loading after intravenous infusion every three weeks.

The pivotal APOLLO Phase III trial demonstrated that patisiran reduced serum TTR concentration by
approximately 80 % and significantly improved the primary endpoint of polyneuropathy severity
compared with placebo, with additional benefits in quality of life and cardiac measures. The drug
was approved at a list price of $450,000 per year, again highlighting the pricing tension inherent
in rare-disease precision medicines.

The LNP delivery technology used in patisiran was a direct ancestor of the LNP formulations
employed in the Moderna and Pfizer-BioNTech mRNA COVID-19 vaccines approved two years later,
illustrating how rare-disease drug development can prefigure transformative platform medicines.