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FDA Approves First-Ever siRNA Therapy

Today FDA approved the first-ever “small interfering RNA” (siRNA) product, marking a significant milestone in the story of RNA interference (RNAi) technology and clearing the way for a new type of therapeutic.  Alnylam® secured approval and Orphan Drug Designation for its siRNA product Onpattro (patisiran), a therapy for the rare hereditary disease transthyretin-mediated amyloidosis in adult patients.  The disease is caused by mutations in a protein called “transthyretin” which leads to symptoms of neuropathic pain, loss of sensation in the hands and feet, and wheel-chair confinement.  In Alnylam’s Phase III clinical trial, Onpattro improved multiple clinical manifestations of the disease and demonstrated safe administration of a siRNA product.

The approval comes after over a decade of pursuing RNAi as a therapy.   A series of big pharma exits from the RNAi space suggested that the technical hurdles associated with bringing a therapeutic siRNA product to market were too great.  In 2011, Pfizer announced it was exiting therapeutic RNAi research and development as part of a global cost-saving restructuring plan.  In 2014, Merck sold the technology and intellectual property it acquired in 2006 at the cost of $1.1 billion in purchasing Sirna Therapeutics to Alnylam for $175 million.  Soon after, it was reported that Novartis sold its decades-long RNAi business in a fire sale to Arrowhead for $35 million.

A key hurdle for realizing the potential of siRNA as a therapy is getting siRNA molecules to the right location in the body.  In order to work, the siRNA must be inside the cell of interest.  This means the siRNA must be transported to the tissue in the body where the target cells reside and then it must cross through the cell’s membrane.  These requirements are generally referred to as “delivery” of the siRNA to the desired location.

What is siRNA and why is its delivery so difficult? 

siRNA is the molecule that carries out the process of RNAi.  RNAi is a natural process that occurs in cells to stop a gene from producing a particular protein.  Proteins are made in carefully prescribed steps: first the DNA sequence of a gene is transcribed into a molecule called a messenger RNA (mRNA); next the mRNA sequence (carrying over the gene’s sequence) is translated into the corresponding amino acid sequence or protein.  siRNA stops the production (and therefore activity) of a protein by interfering with the mRNA and preventing its translation into protein.  siRNA is distinct from other types of biologics, such as antibodies, which bind to already-formed proteins and impact their function or remove them from the body.  The siRNA therapeutic approach – stopping the production of an undesirable protein before it has even been made – has been described as “stopping the flood by turning off the faucet as compared to today’s medicines that simply mop up the floor.”

siRNAs work by degrading mRNA in a highly specific manner.  Once an mRNA sequence of interest is known, the siRNA molecule can be designed with a complementary sequence that is able to bind to the mRNA and cause its destruction.  Without the mRNA, protein synthesis is effectively stopped.  A key feature of siRNA is that one siRNA molecule can degrade many mRNA molecules, making it a potentially powerful way of turning off unwanted protein production.  In the case of Onpattro, the therapeutic siRNA interferes with the production of the protein that causes transthyretin-mediated amyloidosis.

The discovery of RNAi was a major scientific breakthrough.  Science declared it 2002’s Breakthrough of the Year.  In 2006, the Nobel Prize for Physiology and Medicine was awarded to Craig Mello and Andrew Fire in recognition of their discovery of RNAi and its importance to medicine.  In contrast to other therapies, such as small molecules and antibodies, siRNAs can be designed to target the mRNA of any human gene opening up new possibilities for treating disease.

Many companies, like Alnylam, jumped into the RNAi field and brought siRNA drug candidates into the clinic, including Allergan, Sirna Therapeutics, Quark Pharmaceuticals, Zabecor Pharmaceuticals, Calando Pharmaceuticals, Silence Therapeutics, RXi Pharmaceuticals, and Santaris Pharma, among others.  Results were mixed across a range of indications from cancers, asthma, macular degeneration, ocular disorders, and rare hereditary diseases.

Despite the scientific promise and pharma’s investment, siRNA-based therapies faced hurdles, namely delivery.  Delivery proved difficult because siRNAs are relatively large, negatively charged molecules that do not naturally cross through a cell’s outer membrane.  siRNAs are also rapidly excreted from the blood stream when introduced into the body.  Further, siRNAs were found to trigger innate immune receptors (called toll-like receptors) to initiate inflammation, raising concerns about how to safely and selectively transport siRNA to target tissues in the body and avoid unwanted inflammation.

Overcoming delivery to bring forward a new class of therapeutics

Alnylam developed a pipeline of siRNA therapeutic candidates that employ two different delivery approaches.  The first approach is to deliver the siRNA molecule in a lipid nanoparticle.  Lipid nanoparticles naturally accumulate in the liver and are able to cross through the membrane of a cell.  This delivery method is therefore well-suited for protein targets that are found in the liver.  This delivery approach was used for Onpattro to treat transthyretin-mediated amyloidosis because the transthyretin protein is produced predominantly in the liver.

Alnylam’s other late-stage siRNA therapeutic candidates utilize a different delivery approach in which the siRNA is attached to another molecule (e.g., an antibody fragment, receptor ligand, or sugar) that guides the siRNA to the target cell.  Because this approach is not limited to targeting the liver, it opens up the possibility of targeting a wider range of human diseases.  In the case of Alnylam’s late-stage products (Givosiran for acute hepatic porphyrias, Fitusiran for hemophilia, and Inclisiran for hypercholesterolemia), the siRNA is attached to a sugar molecule for target-specific delivery.

With siRNA therapy now a reality and new products on the horizon, more patent disputes involving siRNA are likely as well.  Indeed, Alnylam recently filed a declaratory judgment action against Silence Therapeutics for non-infringement of patents alleged to cover Onpattro.  Alnylam also filed a series of post-grant review (PGR) proceedings at the United States Patent and Trademark Office challenging Silence Therapeutics’ patents directed to siRNA molecules as unpatentable.

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