Multinational pharma's heavy bets, biotech capital market debuts, traditional pharma M&A entry, and potential blockbuster products nearing the finish line – through the first half of 2026, oligonucleotide drugs have firmly held global pharma's attention.

 

The latest progress comes from two pieces of news in the hepatitis B field: at the end of May, GSK announced Phase III data for its ASO drug bepirovirsen, bringing hope for a functional cure for hepatitis B closer. Around the same time, Hengrui Medicine's hepatitis B oligonucleotide drug HRS-5635 officially initiated Phase III clinical trials.

 

Chronic hepatitis B, once considered a "century problem," is now facing a real possibility of a cure under the assault of oligonucleotide technology.

 

Amid this intense activity, TONACEA recently interviewed Liang Zicai, Chairman and CEO of Ribo Life Sciences; Chang Yan, President of InnoStar; and Li Hao, CMO at Kanglonghua (Convalife) Preclinical. From the perspectives of technological landscape, blockbuster drug progress, domestic advantages, cutting-edge approaches, and future evolutionary directions, they systematically articulated the underlying logic for their bullishness on oligonucleotides.

 

Dr. Li Hao, a longtime expert in innovative drug clinical development, offers a clear and rational judgment on this field. His bullishness on oligonucleotides stems not from their ability to treat one specific disease, but from their provision of a generalizable way to treat countless diseases.

 

In his view, oligonucleotides are on the cusp of a breakthrough. During 2026-2027, with multiple blockbuster products targeting major diseases such as hepatitis B, hemophilia, and hypercholesterolemia expected to receive concentrated approvals, the industry will enter a true "harvest period." The following is an exclusive interview with Dr. Li Hao.

 

 

TONACEA 01: How Oligonucleotides Disrupt Traditional Drugs

 

In the history of pharmaceutical R&D, the rise of each new therapy has often been accompanied by a "disruptive" overturning of existing paradigms – small molecules conquered many previously untreatable diseases, and antibodies addressed targets that small molecules "couldn't reach." Today, the emergence of oligonucleotides is ushering in a new round of paradigm change.

 

To use an analogy: antibodies are like fire trucks, arriving after the fire has started; oligonucleotides, on the other hand, remove the flammable materials before a fire can ignite. Dr. Li Hao points out that this logic of precise intervention brings three major disruptive advantages.

 

01 Broader Target Range

Combined, traditional small molecule drugs and antibody drugs can only target approximately 1.5% of protein-coding genes in the human genome.

Antibodies are inherently limited to recognizing proteins on the cell membrane surface or extracellularly, leaving intracellular and nuclear targets untouched. Small molecules can enter cells but mostly act on enzyme active sites, leaving a vast number of "undruggable" targets.

Oligonucleotides are fundamentally different. They can regulate gene expression at the RNA level, covering the entire information flow from transcription to splicing to translation. Theoretically, they can target approximately 80% of the human genome – including transcription factors, non-coding RNAs, and other targets that traditional drugs simply "cannot reach," opening entirely new therapeutic pathways for difficult-to-treat diseases such as cancer and rare genetic disorders.

 

02 Unique Mechanism of Action

Traditional drugs often employ a "passive confrontation" strategy – the pathogenic protein has already been produced, and the drug then inhibits or neutralizes it. Oligonucleotides intervene further upstream: degrading the pathogenic mRNA before it is translated, or altering its splicing pattern, effectively cutting off the production line of the pathogenic protein at its source.

The greatest benefit of this mechanism is the effective evasion of drug resistance. Target mutation is the most troublesome problem for traditional drugs – a single change in protein structure can render an antibody or small molecule ineffective.

Oligonucleotides target the relatively conserved mRNA sequence; as long as the gene sequence remains unchanged, the drug can continue to work. This advantage is particularly prominent in diseases prone to acquired resistance, such as cancer.

 

03 More Efficient R&D Model

Traditional drug R&D requires large-scale, high-throughput screening – lengthy cycles and high costs. Oligonucleotide R&D, in contrast, follows a "sequence-driven" logic: once the disease-causing gene sequence is identified, candidate molecules can be rapidly designed based on the principle of base complementary pairing.
Chemical synthesis processes are well-established, eliminating the need for complex cell culture or protein purification steps. Consequently, the R&D cycle for oligonucleotide drugs is significantly shortened, process scale-up is relatively simple, and production costs are noticeably lower than for antibody drugs.

Furthermore, on the administration side, oligonucleotides demonstrate a long-acting advantage. Traditional antibodies typically require dosing every few weeks. Key breakthroughs in chemical modification and innovative delivery systems have made oligonucleotide drugs less immunogenic, more stable, and with longer half-lives – achieving dosing frequencies of once every six months, a revolutionary improvement in long-term adherence for chronic disease patients.

 

From target range to mechanism of action, from R&D efficiency to administration convenience, oligonucleotides are achieving a comprehensive "disruptive" overturning of traditional drugs.

 

TONACEA 02: Dense Blockbusters – Domestic Strength Takes the Global Stage

 

The sole criterion for determining whether a field is a "hype" or a "trend" is: has it consistently generated profitable products?

 

In 2025, oligonucleotide drugs provided the answer.

 

According to不完全统计, total global sales of marketed oligonucleotide drugs exceeded US$7.1 billion in 2025, a year-on-year increase of nearly 40%. Among these, three products – Amvuttra® (vutrisiran), Spinraza® (nusinersen), and Leqvio® (inclisiran) – entered the "US$10 billion blockbuster" category.

 

In the first quarter of 2026, blockbusters continued to see increased volume. Driven by four self-commercialized siRNA drugs, Alnylam's product revenue reached US$1.036 billion (a 121% increase from Q1 2025), successfully joining the "US$1 billion quarterly revenue club." Novartis's Leqvio also achieved accelerated growth outside the U.S., with Q1 2026 sales reaching US$452 million, a massive 76% year-on-year increase.

 

Dr. Li Hao noted that while commercialized products are advancing strongly, several oligonucleotide drugs in development have also achieved breakthrough progress.

 

On May 27, the CDE website showed that GSK's New Drug Application (NDA) for bepirovirsen injection had been accepted. The application is for the limited-duration treatment of chronic hepatitis B virus (HBV) infection in adults who are currently on nucleos(t)ide analog (NA) therapy, with HBsAg ≤3000 IU/mL, and without cirrhosis.

 

Notably, this is the drug's second NDA submission. Bepirovirsen has now been filed for approval in China, Japan, and the U.S. If approved, this product could become the first six-month, limited-duration treatment option for chronic hepatitis B and serve as a foundational drug for future sequential therapies.

 

Sanofi's fitusiran, a long-acting prophylactic siRNA for hemophilia A/B, restores coagulation balance by lowering antithrombin (AT) levels. It transforms traditional frequent intravenous injections into subcutaneous administration, greatly improving patient adherence. Fitusiran has completed registrational Phase III clinical trials and has been approved in both China and the U.S.

 

Additionally, innovative pipelines such as DYNE-101 (muscle-targeting ASO) for myotonic dystrophy and ION582 (gene activation therapy) for Angelman syndrome have also entered later-stage clinical development.

 

Chinese strength has been particularly impressive in this wave. Dr. Li Hao pointed out that Chinese companies have established global competitiveness in five core areas: hepatitis B, lipid-lowering, anticoagulation, NASH, and C3 complement-related nephropathies, even achieving leadership in some sub-fields.

 

He mentioned that Convalife has recently received visits from CEOs of several multinational pharmaceutical companies. These MNCs are not merely seeking CRO services; they want to understand the clinical progress of China's R&D pipelines, especially nucleic acid drugs, in preparation for future acquisitions, M&A, and collaborations.

 

"China's pharmaceutical innovation has already reached the level of a major power, not only in speed of iteration and cost reduction, but also in the marked shortening of the entire track's maturation and development cycles," he said. In his view, the wave of oligonucleotide out-licensing and global expansion has only just begun, and will continue to grow.

 

TONACEA 03: Full Technological Landscape – The Potential of miRNA

 

As of the end of May 2026, approximately 23 oligonucleotide drugs have been approved globally (including those discontinued), with approximately 20 actually on the market. These include 13 ASOs (including 3 discontinued), 8 siRNAs, and 2 aptamers, covering rare diseases/genetic disorders, cardiovascular diseases, neurological disorders, ophthalmic diseases, infectious diseases, and more.

 

In fact, the landscape extends far beyond these approved classes. Oligonucleotides have developed into a diverse technology matrix. According to不完全统计, there are currently over 740 pipelines globally in development, spanning 12 disease areas, nearly 100 diseases/indications, and covering over 250 targets. Dr. Li Hao systematically outlined the characteristics and prospects of the various technology routes.

 

• ASO (Antisense Oligonucleotide): The most mature technology, with the most pipelines. Can either induce RNase H-mediated mRNA degradation or modulate splicing (e.g., Spinraza for SMA). Highly flexible with broad target coverage.

• siRNA (Small Interfering RNA): Utilizes the cell's natural RNA interference mechanism for highly efficient gene silencing. When combined with GalNAc delivery, achieves organ-level precision targeting and long-acting dosing (once every six months). Currently the most commercially successful route.

• miRNA (microRNA): Mimics or antagonizes endogenous microRNA to regulate complex gene expression networks. Particularly well-suited for multi-target, complex mechanism diseases (e.g., fibrosis, solid tumors, cardiovascular disease).

• saRNA (Activating RNA): Oppositely, targets gene promoter regions to activate endogenous gene expression. Representative candidate ABBV-151 is for chronic hepatitis B, aiming to break immune tolerance.

• circRNA (Circular RNA): Features a covalently closed circular structure, naturally resistant to nuclease degradation with a long half-life. Can serve as a long-acting protein expression platform for vaccines or protein replacement therapies.

• Aptamer (RNA Aptamer): Single-stranded nucleic acids that fold into three-dimensional structures, binding target proteins with high specificity like "chemical antibodies." Pegaptanib for wet AMD is a marketed example.

 

Among these technology routes, Dr. Li Hao is particularly optimistic about the future of miRNA, despite its significant challenges.

 

This optimism is based on several factors. First, a solid scientific foundation – the research on miRNA's epigenetic regulatory mechanisms was awarded the 2024 Nobel Prize in Physiology or Medicine. Second, clinical validation already exists – Abivax's obefazimod (a small molecule upregulating miR-124) has shown positive results in Phase III trials for ulcerative colitis and Crohn's disease, validating the druggability of miRNA regulatory pathways. This is supported by a clear mechanism of action (MOA) and advances in delivery systems.

 

"The biggest difference between miRNA and ASO/siRNA is that miRNA does not target a single gene, but can regulate multiple downstream target genes simultaneously," Dr. Li Hao explained. "This makes it naturally suited for treating complex diseases involving multiple genes – such as liver fibrosis, lung fibrosis, solid tumors, and autoimmune diseases. These conditions are often not caused by a single gene mutation, but by the interplay of multiple signaling pathways, where single-target drugs struggle to be effective."

 

He also mentioned a more cutting-edge direction – research by Professor Miura at LIVIUS. "He found that specific miRNAs could reverse highly malignant cancer cells into MSC/iPSCs, turning them 'from evil to good,' rather than killing them like traditional chemotherapy. This strategy theoretically ensures safety and avoids tumor resistance and relapse. In animal experiments, liver cancer cells were even transformed into normal liver tissue."

miRNA's application scenarios are not limited to serious drugs. Dr. Li Hao offered an example: "A hair growth/hair care product based on a miRNA agonist has already launched. Based on data from 118 patients, the efficacy rate reached 86.8%. It contains no hormones, no shedding phase, and requires application once every 1-2 weeks. A course of five treatments significantly improves adherence. This demonstrates miRNA's potential to crossover into the consumer healthcare space, which is a large and growing field."

 

TONACEA 04: The Dawn of a Golden Age

 

Market, technology, therapeutic areas, collaborations, and paradigm – the共振 of these five dimensions is pushing oligonucleotides toward the dawn of a golden age. From rare diseases to chronic diseases and oncology, from liver targeting to systemic delivery, global giants and innovative drug companies are competing on the same stage, with competition and cooperation existing side-by-side.

 

This is not merely the rise of a class of drugs. When "sequence-driven" replaces "structure screening," when once-every-six-month dosing becomes the new norm in chronic disease management, and when AI algorithms accelerate target discovery, sequence optimization, and drug screening – drastically shortening R&D cycles and improving success rates and precision – oligonucleotides are bringing an entirely new logic of disease intervention.

 

They expand "druggability" from a narrow problem of protein structure to an almost limitless problem of gene sequence identification. Diseases that were once untreatable are now being written, one by one, into the list of oligonucleotide indications.

 

The golden age of oligonucleotides has only just begun.