Market of siRNAs Poised to Expand Beyond 3 Currently Approved Drugs


While only 3 small interfering RNA (siRNA)-based therapies have been approved, the market is poised to expand with 7 other candidates in phase 3 trials.

While only 3 small interfering RNA (siRNA)-based therapies have been approved (patisiran, givosiran, and lumasiran), there are 7 other candidates in phase 3 trials. A review published in Biochemical Pharmacology provided an overview of siRNA therapeutics as they are poised to become a “standard modality of pharmacotherapy.”

RNA interference is a natural mechanism by which eukaryotic cells control gene activity. siRNAs cause targeted gene suppression and allow therapies to target and silence the messenger RNA products of genes, the authors noted.

Creating siRNA-based drugs has been a 20-year process, but in 2018, the FDA approved patisiran, the first siRNA, to treat hereditary transthyretin amyloidosis (hATTR); in 2019, givosiran was approved to treat acute hepatic porphyria; and in 2020, lumasiran was approved to treat primary hyperoxaluria type 1.

“Why did it take so long to fully realize and implement the therapeutic potential of RNA interference? The main challenge to siRNA drug development is site-specific delivery,” the authors explained. “Large anionic siRNA molecules must overcome a variety of physiological barriers to reach the cytoplasm in target cells.”

One of the challenges facing siRNAs is their delivery. They must be delivered to and taken up by their intended target, but they have low bioavailability, requiring a larger dose for absorption, and delivery is compromised by rapid clearance. If they clear these challenges, siRNAs then face a difficult path through the capillary endothelium, and they may accumulate at sites other than the target organs.

Chemically modifying siRNAs and employing various delivery strategies are being utilized to address the myriad of challenges siRNAs face when being delivered and taken up into the target cells. Chemical modifications seek to increase the efficiency and potency of the therapeutics. There are 2 major delivery strategies:

  • Formulation of the siRNA into nanocarriers to allow for the introduction of the therapeutics into target cells
  • Conjugation of the therapy to a targeting ligand binding to a receptor on the target cell

Beyond the 3 drugs already approved, all of which are manufactured by Alnylam Pharmaceuticals, there are another 7 in phase 3 trials.

Vutrisiran, also from Alnylam, would treat hATTR like patisiran. The authors noted that the modifications and delivery system of vutrisiran are more advanced. A phase 1 trial from January 2018 confirmed vutrisiran was well-tolerated with mild to moderate adverse events (AEs). Two phase 3 trials are comparing vutrisiran to patisiran.

Nedosiran is being developed by Dicerna Pharmaceuticals to treat primary hyperoxaluria. The therapy targets the hepatic enzyme lactate dehydrogenase, whereas lumasiran targets the hepatic enzyme glyoxylate oxidase. Dicerna has received Breakthrough Therapy and Rare Pediatric Disease designations from the FDA.

Inclisiran would treat hypercholesterolemia, expanding siRNAs from orphan diseases to more prevalent conditions. According to the authors, “inclisiran is arguably the most promising siRNA therapeutic drug in development in terms of its potential impact.” The drug, being developed by Alnylam and Novartis Pharmaceuticals, inhibits the proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway, which would put it in competition with PCSK9 inhibitors like alirocumab and evolocumab.

Fitusiran, in development by Alnylam and Sanofi Genzyme, is in phase 2 and 3 trials to treat hemophilia A and B. The therapy inhibits the function of anti-clotting factors, thus decreasing bleeding events.

Teprasiran, from Quark Pharmaceuticals and licensed to Novartis, is being developed as a prophylactic treatment for acute kidney injury (AKI) after transplant or cardiovascular surgery. The therapy has undergone several clinical trials and Quark is currently recruiting for a phase 3 trial to test teprasiran against placebo in patients at high risk for AKI following cardiovascular surgery.

Cosdosiran is also from Quark and is being developed to treat nonarteritic anterior ischemic optic neuropathy and primary angle glaucoma. The future of this therapy is uncertain. A phase 2b/3 trial was terminated in August 2020 following an interim analysis. A phase 2 trial concluded July 2015, but results have yet to be published.

Tivanisiran is an siRNA candidate from Sylentis S.A. to treat ocular pain and dry eye disease. In the phase 3 trial HELIX, the therapy failed to meet its primary end points. However, in a subpopulation of patients with dry eye disease and Sjögren’s Syndrome, tivanisiran showed statistically significant improvements compared with placebo.

“Although only three siRNA therapeutics have been approved by the FDA to date, more are sure to follow in the coming years,” the authors wrote.

They highlighted the benefits of siRNAs over other novel therapeutic classes. For instance, siRNAs are relatively less expensive to synthesize and manufacture, and they may be administered as infrequently as biannually, as well as have the potential to be self-administrable.

“Factors like these will become increasingly important as novel therapies are developed for rare indications and patients gain consumer power and choice as to which treatment they utilize,” the authors concluded.


Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong X-B. The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol. Published online January 26, 2021. doi:10.1016/j.bcp.2021.114432

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