Exploring Small Nucleic Acid Drugs: Market Trends and Development Status

Nucleic Acid Drug Market

In recent years, the enthusiasm for small nucleic acid drug research and development has been high, and three heavyweight partnership deals have already been reached in 2024, with a potential total amount of more than ten billion dollars. With the continuous breakthroughs in small nucleic acid R&D technology, small nucleic acid drugs are involved in a wider and wider range of disease areas, from rare diseases to chronic diseases, such as the treatment of high blood lipids Leqvio, the treatment of hypertension Zilebesiran, etc., the milestone drug Leqvio in the first nine months of this year, sales increased by 130% year-on-year to 531 million U.S. dollars, breakthrough of the 1 billion U.S. dollars mark is within reach. There are many investigational small nucleic acid drugs in the clinic, and big pharmaceutical companies such as Novartis, AstraZeneca and Roche have joined the layout of the research, the small nucleic acid field is booming.

Small Nucleic Acid Drugs

Small nucleic acid drugs refer to a class of drugs that use DNA or RNA as carriers or targeting targets that are genetically inhibited, added, replaced, or edited to achieve long-lasting and radical therapeutic effects. This class of drugs mainly includes antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), small activating RNAs (saRNAs), messenger RNAs (mRNAs), and RNA aptamers (Aptamers). Compared with traditional small molecule chemical drugs and antibody drugs, small nucleic acid drugs have the advantages of short research and development cycle, long-lasting effect, high success rate of research and development, not easy to produce drug resistance and wide therapeutic field. They act on the mRNA in the cell through the principle of base complementary pairing to regulate the expression of proteins and realize the purpose of treating diseases. In recent years, with continuous technological breakthroughs, the global market size for small nucleic acid drugs has grown from $10 million in 2016 to $3.25 billion in 2021, with a compound annual growth rate (CAGR) of 217.8%. It is expected that by 2024, the global market size for small nucleic acid drugs will reach $8.6 billion.

The indications for small nucleic acid drugs are wide-ranging, including oncology, rare diseases, viral diseases, kidney diseases, cardiovascular diseases, inflammatory diseases, and metabolic disorders. With an increasing understanding of the molecular mechanisms of diseases, small nucleic acid drugs are expected to be used in the treatment of more complex diseases, such as neurodegenerative diseases, autoimmune diseases, and viral infections.

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FDA Approved Nucleic Acid Drugs in Rare Diseases

According to incomplete statistics, as of now, a total of 19 small nucleic acid drugs have been approved for marketing globally (including those that have been withdrawn from the market). Over 80% of these approvals occurred after 2016. However, three small nucleic acid drugs—Vitravene, Kynamro, and Macugen—approved before 2016, have been withdrawn from the market due to various reasons, including low sales.

Table 1. Small nucleic acid drugs approved for marketing.

Among the approved small nucleic acid drugs, Spinraza, developed by Ionis Pharmaceuticals, is the best-selling drug. Clinical trials for Spinraza began in 2011, and due to its remarkable efficacy, it received FDA approval in December 2016 as the first new drug for treating spinal muscular atrophy (SMA) in both children and adults. Since then, Spinraza has also been approved by the European Medicines Agency (EMA), the Japan Pharmaceuticals and Medical Devices Agency (PMDA), and the National Medical Products Administration (NMPA). Currently, SMA patients in over 50 countries and regions worldwide can use this drug for treatment. In 2023, Spinraza's global sales reached $1.7 billion, and its cumulative sales exceeded $10 billion since its launch in 2016. Previously, most approved small nucleic acid drugs were applied in the field of rare diseases. Leqvio, co-developed by Alnylam and Novartis, is the first and currently the only siRNA drug approved for lowering low-density lipoprotein cholesterol (LDL-C). It was approved in the United States in 2021 and in China in 2023, breaking the limitation of small nucleic acid drugs being used primarily for rare diseases and successfully entering the chronic disease field, marking a significant milestone.

Since its approval, Leqvio's sales have steadily increased. In 2022, its sales reached $112 million, and in 2023, it reached $355 million. According to Novartis' recent financial report, in the third quarter of 2024, Leqvio's global sales grew by 119% year-on-year to $198 million. In the first three quarters of 2024, global sales of Leqvio reached $531 million, a 130% year-on-year increase, showing rapid growth.

Major Deals in Nucleic Acid Drugs in 2024

In recent years, the development of small nucleic acid drugs has been booming. Since the beginning of 2024, several significant acquisitions and partnership agreements have taken place in the small nucleic acid drug field, including:

• January 3: Regeron Pharmaceuticals and Boehringer Ingelheim reached a collaboration agreement worth over $2 billion to jointly develop innovative small nucleic acid therapies for the treatment of non-alcoholic steatohepatitis (NASH) and metabolic-associated steatohepatitis (MASH).
• January 8: Bowen Pharmaceutical announced two exclusive licensing agreements with Novartis for RNAi therapies, with a potential total value of up to $4.165 billion. Bowen Pharmaceuticals will receive an upfront payment of $185 million and be eligible for potential options and milestone payments, along with tiered royalties on commercial sales.
• November 26: Arrowhead Pharmaceuticals and Sarepta Therapeutics reached a collaboration agreement potentially worth over $10 billion. The collaboration covers five clinical-stage and two preclinical programs, targeting up to six siRNA drugs for rare diseases, genetic muscle disorders, central nervous system (CNS) diseases, and lung diseases.

These events highlight the vibrant activity and market potential in the small nucleic acid drug field in 2024. They also reflect the global pharmaceutical industry's strong focus on and investment enthusiasm for small nucleic acid technologies and products.

As clinical-stage products continue to launch, advancements in modification and delivery technologies, and the expansion of indications from rare genetic diseases to broader population-based conditions, the overall market is expected to maintain rapid growth.

Nucleic Acid Drugs Examples in Clinical Pipelines

According to incomplete statistics, approximately 200 small nucleic acid drugs are currently in clinical development globally, primarily consisting of ASO (antisense oligonucleotide) and siRNA (small interfering RNA) drugs. These drugs are being explored for use in common diseases such as chronic conditions, viral infections, cancer, and hepatitis B.

Table 2. Some Clinical Small Nucleic Acid Drugs in Development.

Ulefnersen

Ulefnersen is an ASO drug developed by Ionis Pharmaceuticals, aimed at treating amyotrophic lateral sclerosis (ALS) caused by mutations in the fused sarcoma (FUS) gene. Recently, Otsuka Pharmaceutical and Ionis reached a global exclusive licensing agreement, granting Otsuka the rights to produce and market Ulefnersen. Ulefnersen is currently undergoing a Phase 3 international, multicenter clinical trial involving FUS gene mutation ALS patients (ages 12 and above), with an expected study completion in 2025. A first-in-human study conducted under compassionate use authorization for a 25-year-old patient with FUS p.525L ALS demonstrated significant reductions in both wild-type and mutant FUS protein levels in postmortem tissue, with clinical data showing a significant slowdown in the ALSFRS-R decline rate prior to the patient's death after 12 infusions of Ulefnersen (doses ranging from 20mg to 120mg over 10 months).

Pelacarsen

Pelacarsen, developed by Ionis Pharmaceuticals, is an ASO drug targeting Lp(a). In 2019, Novartis obtained the global exclusive development, manufacturing, and commercialization rights for Pelacarsen. Pelacarsen has been tested in global Phase 3 multicenter trials, including in China, and has been granted "Breakthrough Therapy" designation in China. Earlier Phase 2 clinical studies showed that Pelacarsen could reduce Lp(a) by up to 80%, with a monthly dose of 80mg lowering Lp(a) levels in 98% of patients to below 50 mg/dL. Pelacarsen is now undergoing a pivotal Phase 3 clinical trial, Lp(a) HORIZON, aimed at evaluating the safety and efficacy of Pelacarsen in reducing cardiovascular events in patients with elevated Lp(a) levels. The study has enrolled 8,323 participants, with data expected in 2025.

Danvatirsen

Danvatirsen is an ASO drug co-developed by Ionis Pharmaceuticals and AstraZeneca targeting the signal transducer and activator of transcription 3 (STAT3). It selectively binds to STAT3 mRNA, inhibiting translation for the treatment of head and neck squamous cell carcinoma (HNSCC). In a Phase 1 study conducted in Japan to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of Danvatirsen as a monotherapy and in combination with Durvalumab in advanced solid tumor patients, Danvatirsen showed some disease control and partial responses, with a tendency to reduce STAT3 expression. The SCORES trial, which assessed the combination of Danvatirsen and immune checkpoint inhibitors, achieved the primary endpoint. In non-small cell lung cancer (NSCLC) patients, 4 out of 6 (66.7%) achieved 4 months of disease control, while in pancreatic cancer patients, 4 out of 23 (17.4%) achieved the same. Danvatirsen is now in a Phase 2 trial called PEMDA-HN, comparing Danvatirsen in combination with Pembrolizumab to Pembrolizumab monotherapy in first-line recurrent and/or metastatic HNSCC. The trial plans to enroll approximately 81 patients, with key endpoints being objective response rate (ORR) and various secondary tumor control metrics.

Fitusiran

Fitusiran is an siRNA therapy co-developed by Sanofi and Alnylam Pharmaceuticals, targeting antithrombin III (ATIII) to promote thrombin generation, rebalancing hemostasis and preventing bleeding. Fitusiran uses Alnylam's ESC-GalNAc conjugation technology, enhancing its efficacy and duration of action for subcutaneous administration. It is used for the prophylactic treatment of hemophilia A and B patients, regardless of whether inhibitors to clotting factors are present. Fitusiran showed significant efficacy in the Phase 3 ATLAS-A/B and ATLAS-INH randomized controlled trials, published in The Lancet and The Lancet Hematology. Compared to the control group, patients receiving Fitusiran had a 90% reduction in annualized bleeding rates. The most common adverse events were consistent with the risks associated with severe hemophilia A and B. On May 7, 2024, the injection formulation of Fitusiran received acceptance for review by the National Medical Products Administration (NMPA) in China, potentially leading to its first approval in China.

Zilebesiran

Zilebesiran is an siRNA drug developed by Alnylam Pharmaceuticals, targeting liver-expressed angiotensinogen (AGT). It is composed of an RNA interference molecule covalently linked to an N-acetylgalactosamine (GalNAc) ligand, which binds to a receptor on liver cells for precise delivery. Zilebesiran significantly reduces AGT production in the liver and achieves long-lasting effects by repeatedly utilizing the RNA interference silencing complex (RISC). It is currently in Phase 2 clinical development for the treatment of hypertension in underserved populations. On July 24, 2023, Alnylam announced a strategic partnership with Roche to jointly develop and commercialize Zilebesiran, with a deal value of up to $2.8 billion, including an upfront payment of $310 million. Zilebesiran has met the primary endpoints in two Phase 2 trials, KARDIA-1 and KARDIA-2. In the KARDIA-1 trial, a single dose of Zilebesiran showed significant reductions in 24-hour average systolic blood pressure (SBP) at 3 months. In the KARDIA-2 trial, adding Zilebesiran to standard treatment significantly lowered patients' 24-hour average SBP, with some patients maintaining this effect at 6-month follow-up.

Small nucleic acid drugs have broken through the limitations of rare diseases, with an expanding range of applications in fields such as cancer and chronic diseases, and clinical trials have yielded positive results. With ongoing technological advancements, more small nucleic acid drugs are expected to be approved in the future. As more small nucleic acid drugs are approved and new technological breakthroughs emerge, the market for small nucleic acid drugs is expected to exceed tens of billions of dollars.

Exploring Small Nucleic Acid Drugs: Market Trends and Development Status

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