Eight biotech companies advancing the field of siRNA

Small interfering RNA (siRNA) carries great promise in the biotechnology industry. As an essential component of the RNA interference (RNAi) pathway, siRNA works by degrading target messenger RNA (mRNA) molecules, thereby preventing them from being translated into proteins. This specific mechanism has the potential to treat a wide range of diseases, from genetic disorders and cancers to viral infections. 

Unlike other RNA molecules such as mRNA, which carries genetic information for protein synthesis, or miRNA, which regulates gene expression more broadly, siRNA is designed to target and silence specific genes with precision.

According to Maximize Market Research, the market for siRNA therapeutics is expected to grow from $12.7 billion to $39.2 billion by 2029. Here are eight companies contributing to the field of siRNA.

Alnylam Pharmaceuticals

Founded in 2002 and headquartered in Cambridge, Massachusetts, Alnylam Pharmaceuticals is a leader in RNAi therapeutics. The company leverages its proprietary platforms, the enhanced stabilization chemistry (ESC) platform, and its conjugate delivery platform. 

The ESC platform incorporates chemical modifications to the siRNA molecules, which enhance their stability and reduce the likelihood of degradation within the body. This allows for longer-lasting therapeutic effects and less frequent dosing.

The conjugate delivery platform involves the use of GalNAc (N-acetylgalactosamine) conjugates, which specifically target liver cells. By attaching GalNAc ligands to siRNA molecules, Alnylam can deliver these therapeutics directly to hepatocytes (liver cells) with high precision. This targeted delivery system enhances the efficacy of the siRNA while minimizing off-target effects and potential toxicity.

The biotech company is well-established in the siRNA field and has several commercialized products on the market: 

• ONPATTRO (patisiran): This drug treats hereditary transthyretin-mediated amyloidosis (hATTR). It utilizes the ESC platform to stabilize the siRNA molecule, targeting and silencing the TTR gene to reduce the production of transthyretin protein.
• GIVLAARI (givosiran): Used for acute hepatic porphyria, this therapy reduces the levels of aminolevulinic acid synthase 1 (ALAS1), which is involved in the production of toxic heme precursors. The GalNAc conjugate ensures liver-specific delivery.
• OXLUMO (lumasiran): This drug targets hydroxyacid oxidase 1 (HAO1) mRNA to reduce oxalate production in patients with primary hyperoxaluria type 1. The GalNAc-siRNA conjugate enhances delivery to liver cells where oxalate is produced.
• Leqvio (inclisiran): Designed to lower low-density lipoprotein cholesterol (LDL-C) levels and is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who require additional LDL-C lowering.
• AMVUTTRA (vutrisiran): it is an RNAi therapeutic for the treatment of hATTR with polyneuropathy in adults. Approved by the U.S. Food And Drug Administration (FDA) in June 2022, AMVUTTRA is designed to reduce the production of TTR protein, which misfolds and accumulates in tissues, causing the symptoms of hATTR.

Since it was founded in 2002, the biotech has raised close to $4 billion. It continues to expand its pipeline with ongoing clinical trials for new indications, including zilebesiran for which Alnylam recently announced positive phase 2 clinical trials result for hypertension. 

Aro Biotherapeutics

Founded in 2017 and headquartered in Philadelphia, Pennsylvania, Aro Biotherapeutics specializes in developing tissue-targeted genetic medicines. The company’s proprietary Centyrin technology enables the precise delivery of therapeutic agents to specific cells.

Aro’s Centyrin technology involves small, stable proteins that are engineered to bind specifically to disease targets. This technology is particularly effective for delivering siRNA to extra-hepatic tissues. Centyrin-siRNA conjugates allow for targeted delivery to tissues like muscle, where traditional siRNA therapies struggle to reach. This targeted approach enhances the efficacy and safety profile of siRNA therapies by minimizing off-target effects and ensuring that the therapeutic molecules reach the intended cells.

The company’s lead candidate, ABX1100, is a Centyrin-siRNA conjugate targeting Pompe disease, a rare, inherited metabolic disorder caused by mutations in the GAA gene. This gene mutation leads to a deficiency of the enzyme acid alpha-glucosidase, which is crucial for breaking down glycogen into glucose. As a result, glycogen accumulates in the lysosomes, causing progressive damage to muscle and nerve cells throughout the body. 

This therapy is currently in phase 1 clinical trials and has received both orphan drug designation and rare pediatric disease status from the FDA. ABX1100 works by targeting glycogen synthase 1 (Gys1) mRNA in muscle tissues, reducing the toxic glycogen buildup that characterizes Pompe disease.

Aro Biotherapeutics has raised significant funding, with a recent $41.5 million series B financing round in November 2023. The company recently started its first-in-human clinical trial for ABX1100, with initial findings expected in 2024.

Arrowhead Pharmaceuticals

Established in 2003 and based in Pasadena, California, Arrowhead Pharmaceuticals specializes in developing RNAi-based therapies.

Arrowhead’s Targeted RNAi Molecule (TRiM) platform is designed to enable precise delivery of siRNA molecules to specific tissues. The TRiM platform optimizes siRNA stability, reducing off-target effects and improving therapeutic outcomes. This platform uses a modular approach, allowing different chemical components to be swapped in and out to best suit the target and disease.

The company’s lead candidates include:

• ARO-AAT (Fazirsiran): In phase 2 trials, this drug targets alpha-1 antitrypsin deficiency by silencing the defective gene responsible for producing the faulty protein, reducing liver inflammation and damage.
• ARO-HBV: Aimed at treating chronic hepatitis B by targeting and degrading viral mRNA, reducing viral load and liver inflammation. ARO-HBV is in phase 2.
• Plozasiran: This candidate is in phase 3 trials for the treatment of hypertriglyceridemia and mixed dyslipidemia. It targets genes involved in lipid metabolism to reduce triglyceride levels and improve lipid profiles in patients with cardiovascular risks. The company reported positive topline results from the pivotal phase 3 trials earlier this week.
• ARO-DM1: Focused on myotonic dystrophy type 1 (DM1), ARO-DM1 targets the DMPK gene and is in phase 1 trials. It aims to halt the progression of DM1 by reducing toxic RNA buildup in muscle tissues.

Arrowhead collaborates with pharmaceutical giants like Takeda, Amgen, and GSK to co-develop and commercialize RNAi therapies.

Dicerna Pharmaceuticals (acquired by Novo Nordisk)

Dicerna Pharmaceuticals, founded in 2006, is now a subsidiary of Novo Nordisk. The company focuses on developing RNAi-based therapies to address genetic and rare diseases.

Dicerna’s GalXC RNAi technology employs a structure where siRNA molecules are chemically conjugated to a GalNAc ligand. This ligand targets receptors highly expressed in liver cells, ensuring the siRNA is efficiently delivered to the liver. Once inside the liver cells, the siRNA is released, where it can bind to and degrade the target mRNA, reducing the production of disease-causing proteins.

The two key candidates that motivated Novo Nordisk to acquire the siRNA company in addition to its technology are Rivfloza and Belcesiran. 

The FDA approved Rivfloza (nedosiran) for treating primary hyperoxaluria type 1 (PH1) in children 9 years and older and adults with relatively preserved kidney function. PH1 is an inherited disorder caused by a deficiency of the liver enzyme alanine-glyoxylate aminotransferase (AGT). This enzyme deficiency leads to the overproduction of oxalate, a substance that combines with calcium to form insoluble calcium oxalate crystals. These crystals can accumulate in the kidneys and urinary tract, leading to kidney stones and progressive kidney damage. Rivfloza is a once-monthly subcutaneous therapy designed to lower urinary oxalate levels by targeting the liver enzyme lactate dehydrogenase, crucial in oxalate production. 

Currently in phase 2 clinical trials, Belcesiran targets alpha-1 antitrypsin deficiency (AATD) by silencing the mutant gene responsible for the disease, reducing liver damage. AATD is a genetic disorder caused by mutations in the SERPINA1 gene. AATD primarily affects the liver and lungs, leading to conditions such as liver cirrhosis and emphysema.

Prior to its acquisition, Dicerna secured a substantial total funding of $420.5 million. Following its acquisition by Novo Nordisk, Dicerna’s technologies and pipeline have been integrated into Novo’s broader therapeutic programs, expanding the application of RNAi therapies.

DTx Pharma (acquired by Novartis)

Founded in 2017, DTx Pharma is a biotechnology company that focuses on developing RNA-based therapies using its proprietary Fatty Acid Ligand Conjugated OligoNucleotide (FALCON) platform. In July 2023, Novartis acquired the siRNA company for an upfront payment of $500 million, with potential milestone payments bringing the total value up to $1 billion. 

The FALCON platform enhances the delivery, stability, and potency of siRNA molecules by conjugating them with fatty acids. This modification improves the biodistribution and cellular uptake of siRNA, enabling efficient gene silencing in tissues beyond the liver, such as the central nervous system and muscles. This approach leverages the natural uptake mechanisms of cells for fatty acids, thereby “tricking” cells into absorbing the siRNA for targeted gene repression.

The lead candidate, DTx-1252, targets Charcot-Marie-Tooth disease type 1A (CMT1A), a genetic disorder affecting the peripheral nerves. It works by silencing the PMP22 gene, which is overexpressed in CMT1A patients. A month before the acquisition, DTx-1252 was granted orphan drug designation by the FDA and is currently in preclinical development, with plans to start clinical trials in the near future.

Eleven Therapeutics

Founded in 2020 and with activities in the U.K., the U.S., and Israel, this biotech company focuses on developing durable siRNA therapies through a combination of chemistry and artificial intelligence.

Eleven Therapeutics employs its proprietary TERA platform, which integrates parallel combinatorial chemistry with AI algorithms to design and optimize RNA molecules. The platform uses a high-throughput split-pool synthesis process to generate a vast library of chemically modified RNA molecules. Each molecule is tagged with a DNA barcode, enabling precise tracking and analysis of its structure-activity relationship (SAR).

The process involves the following key steps:

• Split-pool synthesis: Millions of RNA molecules are synthesized with various chemical modifications, each attached to DNA barcodes that record their chemical identities.
• Cell incubation: The modified RNA molecules are incubated with cells, where they exert their therapeutic effects.
• High-throughput assays: The effects of these molecules are measured in each cell using high-throughput assays.
• AI analysis: Data from the assays are used to train artificial intelligence (AI) models, which decipher the SAR and optimize the RNA modifications for better therapeutic outcomes.

Eleven Therapeutics raised $22 million in seed funding in 2022, including a substantial contribution from the Bill & Melinda Gates Foundation.

Switch Therapeutics

Founded in 2020 and based in South San Francisco, California, Switch Therapeutics pioneers the CASi (Conditionally Activated siRNA) platform, integrating nucleic acid nanotechnology and RNAi. Switch Therapeutics officially launched with an impressive $52 million series A round in March 2023.

The CASi platform combines properties of both single and double-stranded RNAs to enable efficient self-delivery, enhanced potency, and cell-selective RNAi activity. CASi molecules are designed to be activated only under specific cellular conditions, ensuring that the siRNA is delivered and activated only in target cells. This specificity reduces off-target effects and enhances the therapeutic index of the siRNA therapy.

The siRNA company is initially focused on developing treatments for neurodegenerative diseases but also works on central nervous system diseases. The biotech’s siRNA programs are still at the preclinical stage.

Wave Life Sciences

Wave Life Sciences was founded in 2012 and is headquartered in Cambridge, Massachusetts. It is a clinical-stage biotechnology company focused on developing RNA-targeting therapeutics. The company’s proprietary PRISM platform integrates multiple RNA technologies, including RNAi, RNA editing, splicing, and antisense silencing.

The company employs siRNA constructs enhanced with GalNAc conjugation, which improves targeted delivery to liver cells. This method leverages the natural uptake pathways of cells, enhancing the precision and effectiveness of siRNA therapies.

The biotech’s INHBE program targets metabolic disorders, including obesity. Utilizing Wave’s GalNAc-siRNA technology, the INHBE program has shown promising preclinical results, including substantial weight loss and reduction in visceral fat in animal models. The program is expected to enter clinical trials in early 2025.

Wave Life Sciences has a significant partnership with GSK, focusing on siRNA and RNA editing programs. GSK has selected two siRNA programs to advance to development candidates, utilizing Wave’s GalNAc-siRNA format for hepatology applications. The collaboration with GSK includes the development of up to eight RNA-targeting programs, with Wave leading the research up to the investigational new drug (IND) stage. 

SiRNA technology is here to stay

The field of siRNA therapeutics is poised for substantial growth. This rapid expansion is driven by advancements in RNAi technology, its specificity in gene silencing, and the successful approval and commercialization of several siRNA-based drugs.

Key players like Alnylam Pharmaceuticals have paved the way with FDA-approved therapies such as ONPATTRO or GIVLAARI. Moreover, collaborations between biotech companies and pharmaceutical giants, such as the partnership between Wave Life Sciences and GSK, show the potential of siRNA therapies.

Despite the promising outlook, the field of siRNA therapeutics faces several challenges. One of the primary hurdles is the effective delivery of siRNA molecules to target cells. The hydrophilic and negatively charged nature of siRNA makes it difficult for these molecules to cross cell membranes and reach the cytoplasm. Various delivery systems, such as lipid nanoparticles (LNPs) and GalNAc conjugates, have been developed to enhance cellular uptake and target specificity, but improvements are still needed.

Another challenge is the potential for off-target effects and immune responses. Chemical modifications to the siRNA structure can help mitigate these issues, enhancing stability and reducing immunogenicity. Ongoing research is focused on refining these modifications and developing more sophisticated delivery systems to overcome these barriers.