Oligonucleotide drugs follow a classic path for novel therapies: proof-of-concept in rare diseases, then gradual expansion into large indications.

The Alnylam–Tenaya partnership is the latest illustration of this path. With top-tier RNAi delivery and development platforms, Alnylam needs a more precise “navigator” in cardiovascular-metabolic diseases to identify truly pathogenic genes—capabilities Tenaya provides through human genetics-based target discovery.

This is not speculative. In 2025, Alnylam’s Amvuttra completed a successful leap from rare diseases to mainstream cardiovascular markets.

• On March 23, 2025, the FDA approved Amvuttra for transthyretin amyloidosis cardiomyopathy (ATTR-CM), expanding its indication from neurology to cardiovascular care and entering the mainstream heart failure market.
• Previously indicated for hereditary transthyretin-mediated amyloidosis polyneuropathy (ATTR-PN), Amvuttra served a niche market of 50,000–100,000 global patients, with a market ceiling of roughly $3–5 billion.
• ATTR-CM, while still rare, affects about 150,000 patients worldwide with rising diagnosis rates, exponentially expanding Amvuttra’s market potential. Analysts project the ATTR-CM market to exceed $11.2 billion by 2030.

Amvuttra’s superior safety and convenient administration propelled it from a rare neuropathy treatment to a large cardiovascular market, establishing the TTR segment as the largest product market in oligonucleotide therapeutics.

• In 2025, Amvuttra achieved **$2.314 billion in sales**, up 138.31% year-over-year, becoming the first oligonucleotide drug to surpass $2 billion in annual revenue.
• With four self-commercialized siRNA drugs (Amvuttra, Onpattro, Givlaari, Oxlumo), Alnylam recorded $2.987 billion in product revenue in 2025, an 81% year-over-year increase.

• First-ever full-year profitability: $3.714 billion in revenue, $314 million in GAAP net income.
• 2026 revenue forecast: approximately $5 billion, with TTR products contributing $4.4–4.7 billion.

Novartis’s Leqvio (inclisiran)—the world’s first ultra-long-acting siRNA lipid-lowering drug—joined the blockbuster club, with 2025 sales surging to $1.198 billion, up 57% year-over-year.

Its significance goes beyond sales: it proved oligonucleotides can succeed in chronic diseases. Hyperlipidemia, hypertension, diabetes, and obesity represent billion-patient markets. Leqvio’s success lifted the industry ceiling: oligonucleotides are not just orphan drugs, but future mainstream chronic therapies.

Antisense oligonucleotide (ASO) leader Ionis also reached a milestone: its first self-commercialized product Tryngolza (olezarsen) generated $105 million in its debut year (2025).

In a pivotal Phase III trial for severe hypertriglyceridemia (sHTG), the drug reduced acute pancreatitis risk by 85%, prompting Ionis to raise its peak sales forecast from over $1 billion to over $2 billion, positioning it as the next potential blockbuster.

In aggregate, the 2025 global oligonucleotide new drug market reached $7.122 billion, growing 39.9% year-over-year. With three blockbusters already established, commercialization has entered a high-growth phase.

Every indication expansion in oligonucleotide drugs relies on foundational technological iteration.

In 2026, novel extra-hepatic delivery technologies targeting adipose tissue, CNS, and other organs are expected to achieve 0-to-1 clinical validation, expanding applications from traditional liver targeting to metabolic, neurological, and other large therapeutic areas.

In January, Arrowhead released preliminary Phase I/IIa data for two obesity therapies: ARO-INHBE and ARO-ALK7.

• In patients with obesity and type 2 diabetes, combining ARO-INHBE with tirzepatide doubled weight loss and tripled reductions in visceral, total, and liver fat compared to tirzepatide alone.
• ARO-ALK7 provided the first human evidence that the Activin E/ALK7 pathway (a genetically validated fat-storage regulator) can be targeted to improve body composition and enhance weight loss beyond tirzepatide monotherapy.

This breakthrough validates Arrowhead’s adipose delivery platform and opens opportunities for other cardiovascular-metabolic targets in fat tissue.

Programs targeting muscle, CNS, lung, and adipose tissue are in clinical stages, while kidney and cardiac delivery remain preclinical. These advances mark extra-hepatic oligonucleotides’ shift from technical validation to multi-tissue, multi-target clinical realization, supporting commercial expansion and vast market potential.

Breakdown by Tissue

1. Muscle: Avidity’s deldesiran and delbrax are in Phase III for rare muscle diseases.
2. CNS: Ionis has multiple Phase III programs (zilganersen, ION582) for rare neurological disorders; Alnylam and Arrowhead are developing early-stage assets for Alzheimer’s disease.
3. Lung: Arrowhead’s ARO-RAGE (asthma) is in Phase II.
4. Adipose: Arrowhead’s ARO-ALK7 (obesity) is in Phase I/IIa.

Chinese companies are also narrowing the technology gap through independent innovation and partnerships.

• Ribobio unveiled its RiboPepSTAR™ peptide-conjugation technology at ASN Kidney Week 2025, enabling kidney-specific siRNA delivery and precise gene silencing in renal cells, creating a new path for chronic kidney disease (CKD). Preclinical studies showed up to 80% gene silencing in proximal tubular cells across rodents and non-human primates (NHPs), with improved efficacy endpoints in diabetic and CKD models.
• ShengYin Therapeutics developed the proprietary LEAD™ extra-hepatic delivery platform, enabling efficient, specific delivery to adipose, muscle, and immune cells via receptor-mediated targeting.

In early February 2026, Genentech (Roche) entered a global R&D collaboration and license agreement with ShengYin for an RNAi therapy, with a $1.5 billion total deal value including a $200 million upfront payment.Previously, in December 2025, ShengYin signed a similar RNAi deal with Eli Lilly worth up to $1.2 billion in milestones.Back-to-back licensing with two top pharma companies underscores the unique value of ShengYin’s extra-hepatic platform.

Other Chinese firms—Fuyuan Pharmaceutical, Yuekang Pharmaceutical, Frontier Biotech, Betta Pharmaceuticals, and HitGen—are pursuing extra-hepatic strategies across tissues. Sunshine Novo is entering AOC oligonucleotides via partnerships.Leading companies with platform R&D capabilities and technological expertise are expected to lead value re-evaluation.

Beyond extra-hepatic delivery breakthroughs, 2026 will be a highly catalyst-rich year for the global oligonucleotide sector.

Multiple programs are approaching Phase III data readouts and NDA filings, covering core targets including ApoC3, Lp(a), HBV, and CFB, across cardiovascular-metabolic diseases, hepatitis B, IgA nephropathy, and other major indications.

Positive data will further validate oligonucleotide efficacy and developability, strengthening industry confidence in chronic disease applications.

Hepatitis B

GSK will present Phase III data (B-Well 1 & B-Well 2) for its ASO hepatitis B drug Bepirovirsen at academic conferences and plans for global regulatory submissions in Q1 2026.

As the first oligonucleotide to complete Phase III for chronic hepatitis B, Bepirovirsen has received:

• FDA Fast Track Designation (US)
• Breakthrough Therapy Designation (China)
• SENKU designation (Japan, for accelerated review)

On February 26, 2026, GSK announced that Japan’s Ministry of Health, Labour and Welfare (MHLW) had accepted Bepirovirsen’s NDA for chronic hepatitis B in adults. It could become the world’s first functionally curative therapy for chronic hepatitis B.

Weight Loss & Neurology

• Wave Life Sciences and Arrowhead will update weight-loss oligonucleotide data.
• Alnylam will report four clinical datasets, including preliminary obesity data for an ALK7-targeting siRNA in late 2026.
• Arrowhead’s tau-targeting ARO-MAPT for Alzheimer’s disease will release initial data in late 2026.

ARO-MAPT is Arrowhead’s first RNAi therapy using a novel delivery system that crosses the blood–brain barrier via subcutaneous injection and achieves deep target gene knockdown in the CNS. By silencing the MAPT gene and reducing tau accumulation, ARO-MAPT has the potential to slow or halt progression in early Alzheimer’s disease.

Chinese Companies

In late February, CSPC Pharmaceutical registered two Phase III trials for SYH2053 (CTR20260564, CTR20260549) in primary hypercholesterolemia and mixed dyslipidemia.

Shortly after, Ribobio announced that its PCSK9 siRNA RBD7022/QLC7401, developed with Qilu Pharmaceutical, completed Phase III trial registration (NCT07441317) in China.

Both candidates target the same PCSK9 pathway as inclisiran. As PCSK9 siRNA development intensifies, these are among the first domestic PCSK9 siRNAs to enter Phase III.

Conclusion

The convergence of commercial, technological, and clinical progress outlines a clear trajectory for oligonucleotides moving into the mainstream:

• Commercial success proves market value.
• Extra-hepatic delivery unlocks therapeutic potential.
• Dense clinical data continuously validates platform capabilities.

This is no longer about a single drug breakthrough, but an industry-wide inflection point of self-proving.As leaders turn profitable, chronic disease markets embrace the modality, and longstanding technical barriers fall, oligonucleotide drugs are shifting from “the next big possibility” to “today’s reality”.