Nucleic acid drugs, also known as oligonucleotide therapeutics, typically consist of nucleotide sequences up to 30 base pairs in length. Their primary mechanism of action involves specific nucleotide sequences targeting mRNA to silence gene expression of target proteins,  thereby achieving therapeutic effects. Narrowly defined, nucleic acid drugs refer to small interfering RNA  (siRNA) therapies. However, in a broader sense, they encompass antisense oligonucleotides (ASO), microRNAs (miRNA), small activating RNAs (saRNA), RNA aptamers, and more. Currently, the most commonly developed and researched nucleic acid drugs are siRNA and ASO therapies.

Figure 1. Types of nucleic acid drugs [1]

Approved Nucleic Acid Therapeutics

Although nucleic acid drugs have existed since the launch of the antisense oligonucleotide (ASO) Vitravene in 1998, their journey to clinical and commercial success has been challenging.

Early RNA Therapy (1998):

• • The first RNA-based therapy, Vitravene (an ASO), was launched in 1998.
• • Vitravene was withdrawn a few years after approval due to low demand and poor sales.

Slow Market Growth (1998-2016):

• • For nearly two decades after Vitravene’s release, the RNA market remained small with few new product approvals.

Revival of RNA Therapies (2016 Onwards):

• • In 2016, Spinraza was approved for treating spinal muscular atrophy.
• • In 2018, the first siRNA, Onpattro, was launched.

Impact of the COVID-19 Pandemic (2020 - Now)

• • The development of COVID-19 vaccines played a key role in advancing mRNA technology. The success of mRNA vaccines spurred renewed interest in RNA technologies, leading to an 11-fold increase in mergers and acquisitions (M&A) activity between 2020 and 2021.

To date, there have been 20 FDA- and/or EMA-approved nucleic acid drugs, containing 12 ASO drugs, 6 siRNA drugs, and 2 aptamers (including 3 products that have been withdrawn from the market). The majority of approvals have been for the treatment of rare disease indications, the successful commercialization also fulfills the original intention of addressing clinical requirements and pain points. However, it also reveals the current lack of indications with large patient populations in the nucleic acid drug market.

Table. Approved nucleic acid drugs

Statistics show that over 100 nucleic acid drugs are currently in clinical trials worldwide. These drugs target a range of conditions, including cardiometabolic disorders, cancer, CNS disorders, resoiratory system disorders, ophthalmological disorders and others.  

Figure 2. Pipelines for nucleic acid therapeutics. [1]

Potential Blockbusters of Nucleic Acid Therapeutics

Spinraza

Spinraza, developed by Ionis and Biogen, is the world's first drug approved for treating spinal muscular atrophy (SMA), which can alter the splicing of SMN2 pre-mRNA, thereby increasing the production of full-length SMN protein. SMA is a rare, life-threatening genetic disorder characterized by muscle weakness and atrophy due to the degeneration of motor neurons. 

In 2022 and 2023, Spinraza's global sales reached $1.794 billion and $1.741 billion, respectively, with cumulative sales exceeding $10 billion since its launch.

According to the U.S. National Center for Biotechnology Information, Spinraza is priced at $118,000 per injection in the U.S., bringing the first-year treatment cost to $708,000, followed by $354,000 annually. Despite its high cost, the demand for Spinraza remains strong.

Leqvio

On December 22, 2021, the FDA approved Leqvio, an siRNA drug developed by Novartis and Alnylam, for the treatment of atherosclerotic cardiovascular disease (ASCVD). Leqvio is the first nucleic acid drug for chronic conditions, targeting PCSK9 mRNA to induce its degradation, thereby reducing the expression of the PCSK9 protein and lowering low-density lipoprotein cholesterol (LDL-C) levels. Based on Alnylam’s ESC platform and utilizing GalNAc conjugation technology to target the liver, Leqvio achieves sustained effects through subcutaneous injection.

Figure 3. Structure of Leqvio

Leqvio’s long-lasting effect may improve patient compliance. While statins require daily dosing and monoclonal antibodies need biweekly injections, Leqvio only requires one subcutaneous injection every six months, significantly reducing the treatment frequency and potentially leading to better patient outcomes.

Izervay

On August 5, 2023, Iveric Bio announced that the FDA approved Avacincaptad pegol (Izervay) for treating geographic atrophy (GA). Earlier in May, Astellas acquired Iveric Bio for $5.9 billion, securing rights to Izervay, a pegylated RNA aptamer that binds to and inhibits complement protein C5.

Figure 4. Structure of Izervay

Overactivity of the complement system and the C5 protein are suspected to play a critical role in the development and growth of scarring and vision loss associated with GA secondary to AMD. Izervay, as a complement C5 inhibitor, reduces complement activity. Clinical trials showed a significant reduction in GA progression, with a 35% decrease in the first year of treatment, and Izervay is the first drug to demonstrate such results across two Phase III trials.

As a global partner, Biopharma PEG can supply commercial quantities of high-quality functionalized PEGs, which are essential for your PEGylated nucleic acid therapeutics.

References:
[1] https://www.iqvia.com/blogs/2023/11/rna-therapeutics-rewriting-the-script-of-medical-treatments
[2] Migliorati JM, Jin J, Zhong XB. siRNA drug Leqvio (inclisiran) to lower cholesterol. Trends Pharmacol Sci. 2022 May;43(5):455-456. doi: 10.1016/j.tips.2022.02.003. Epub 2022 Mar 17. PMID: 35307191; PMCID: PMC9802187.

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