Sector Deep Dive | In-Depth Research on the Small Nucleic Acid Segment

▌Research Report Introduction

Small nucleic acid therapeutics (siRNA/ASO), hailed as the "third revolutionary drug class" following small molecules and antibodies, will face a wave of clinical, regulatory, and commercial catalysts in the second half of 2026. Meanwhile, extrahepatic delivery (to the CNS, muscle, and kidneys) is emerging as the core battleground for the next round of valuation re-rating.

▌Research Report Summary:

·Mechanism of action, technical barriers, and advantages of small nucleic acid drugs.

·Comparison between ASO and siRNA.

·Two key directions—chronic diseases and extrahepatic targeting—and their investment theses.

·Three spotlight companies:$Ionis Pharmaceuticals (IONS.US)$、$Arrowhead Pharmaceuticals (ARWR.US)$、$Dyne Therapeutics (DYN.US)$ in-depth insights.

▌Key Takeaways

1. Breakthrough in technological paradigm:Small nucleic acid therapeutics target mRNA, enabling intervention at disease targets previously considered "undruggable" by conventional drugs (only 1.5% of proteins are accessible to small molecules or antibodies → 70% of non-coding RNAs can be modulated by small nucleic acids). Additionally, siRNA leverages the RISC complex’s catalytic cycle to achieve long-acting dosing regimens—such as once-every-six-months injections—addressing the critical issue of patient adherence in chronic diseases.

2. Commercialization boom in chronic diseases + extrahepatic delivery as the next source of premium valuation:GalNAc-conjugated siRNA has matured for hepatic targeting (with crowded pipelines in PCSK9, Lp(a), and APOC3; Alnylam’s L96 patent expires on August 24, 2028). Lp(a) and AGT-targeted hypertension therapies represent the highest near-term upside catalysts with data readouts expected in 2026–2027. Three extrahepatic platforms—AOC (muscle), C16 (CNS/adipose), and POC (CNS/kidney)—are pivotal for potential re-rating of valuations.

3. Three investment theses:① Commercial ramp-up in chronic diseases (lipid disorders, hypertension, obesity, MASH); ② Platform companies focused on extrahepatic delivery (with muscle/CNS data readouts expected within 6–18 months); ③ Differentiated biotechs with pipelines attractive for potential premium acquisition by Big Pharma (benchmark: Novartis’ $12 billion acquisition of Avidity at a 46% premium).

Chart 1: Summary of key technological directions in small nucleic acid therapeutics

Source: PubMed, compiled by Futu Securities

▌ Overview of Oligonucleotide Therapeutics

Oligonucleotide therapeutics represent the third class of revolutionary drugs following small-molecule drugs and antibody drugs.third class of revolutionary drugsTraditional drugs primarily act at the protein level, whereas oligonucleotide therapeutics can directly modulate gene expression through complementary base pairing, thereby suppressing the production of disease-related pathological proteins at the source or regulating specific RNAs to achieve therapeutic effects.

Oligonucleotide therapeutics mainly include two types: antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). Both target specific RNA sequences but differ significantly in mechanism of action, delivery methods, and therapeutic area focus:

– siRNA：Double-stranded RNA, primarily active in the cytoplasm, induces mRNA degradation and gene silencing via the RISC complex. It offers high catalytic efficiency and supports long-acting dosing, with current commercial applications heavily concentrated in liver-targeted indications.

– ASO：Single-stranded DNA/RNA analogs that function in both the nucleus and cytoplasm, offering broader functionality—enabling gene silencing, splicing modulation, translation inhibition, and targeting of non-coding RNAs—with advantages in central nervous system and muscle tissue applications.

Chart 2: Summary of key technological directions in small nucleic acid therapeutics

The technological barriers of small nucleic acid therapeutics primarily consist of three layers:

1. Sequence design:relatively lowLowerOnce the target mRNA sequence is publicly available, drugs can theoretically be designed based on the principle of base complementarity.

2. Chemical modification:BarriershighThis area faces significant patent barriers. Mainstream siRNA technologies include GalNAc conjugation and ESC technology; ASOs primarily employ third-generation modifications such as LNA and PMO.

3. Delivery technology:The current mature approach is GalNAc-siRNA for liver-targeted delivery, with future development focusing onextrahepatic targetingincluding AOC delivery to muscle and heart, and POC delivery to the lungs and central nervous system.

▌Key Company Assessments and Outlook

The small nucleic acid sector will entera period of intensive catalysts in the second half of the year，Ionis (IONS.US)、Arrowhead (ARWR.US)、Dyne Therapeutics (DYN.US) and other companies will face critical validation points around regulatory approvals, clinical data readouts, and M&A expectations.

-$Ionis Pharmaceuticals (IONS.US)$：Earlier underperformance from the ATTR-CM and Tau ASO pipeline data has largely been priced into the stock. Key catalysts in the second half include Tryngolza’s commercial ramp-up, Zilganersen’s PDUFA date (September 22, 2026), and pelacarsen’s Phase III data, providing a foundation for a potential rebound.

-$Arrowhead Pharmaceuticals (ARWR.US)$：The TRiM platform represents a cutting-edge approach to extrahepatic delivery, with key milestones ahead for Redemplo (sHTG Phase III), ARO-MAPT (CNS), and obesity programs. Positive ARO-MAPT data could drive a reassessment of the platform’s value and valuation narrative, though near-term sentiment is weighed down by SRPT’s financial risks.

- $Dyne Therapeutics (DYN.US)$：As a leading player in the AOC space targeting rare muscle diseases, Dyne differentiates itself from Avidity through its pipeline focus (DMD exon 51 vs. exon 44) and holds a robust cash reserve of approximately USD 755 million. Avidity’s acquisition by Novartis at USD 12 billion—a 46% premium—has established a clear valuation benchmark, supporting expectations for a potential M&A premium for Dyne.

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