Ushering in a New Era of Lipid Management – Hongene Empowers Oligo Theraputics to Expand into Metabolic Diseases

Hypercholesterolemia is one of the most common chronic metabolic disorders. Its core characteristic is abnormally elevated levels of "bad cholesterol," or low-density lipoprotein cholesterol (LDL-C), which can form atherosclerotic plaques within blood vessel walls, gradually leading to serious cardiovascular and cerebrovascular diseases such as myocardial infarction and stroke.

The "Chinese Guidelines for Lipid Management (2023 Edition)" indicate that the dyslipidemia rate among Chinese adults has exceeded 35.6%. Data released by the US CDC in 2023 also noted that over 25.5% (approximately 63.1 million people) have LDL-C levels exceeding 130 mg/dL (the normal level is below 100 mg/dL). Small molecule drugs like statins are the current first-line treatment. However, due to issues such as poor daily medication adherence, side effect intolerance, and efficacy plateaus, a significant number of patients still cannot effectively control their cholesterol levels.

Against this backdrop, Inclisiran emerged as the world's first small nucleic acid drug applied to hypercholesterolemia. Inclisiran is an siRNA drug developed through a collaboration between Alnylam and Novartis. By targeting PCSK9 gene mRNA, the drug blocks PCSK9 protein synthesis, thereby increasing LDL receptor levels and continuously clearing LDL-C from the blood. The launch of this drug signifies the first formal "crossover" of oligonucleotide theraputics into the realm of high-prevalence, chronic mass diseases, moving beyond being the exclusive domain of niche rare diseases.

More importantly, in late July 2025, the US FDA officially approved Inclisiran as a preferred monotherapy for adult patients with hypercholesterolemia, no longer mandating combination use with statins. This change, while seemingly subtle, has profound implications:

1. Significant Expansion of the Treatable Population: From being limited initially to patients with ASCVD (Atherosclerotic Cardiovascular Disease) or those statin-intolerant, it is now expanded to a broader population of patients with hypercholesterolemia.
2. Breaking Path Dependency in Treatment: Patients no longer need to experience statin treatment failure before considering Inclisiran; they can use this drug from the outset.

This FDA label update marks the first time a small nucleic acid drug has become a "starting drug" for chronic disease treatment, also foreshadowing the future positioning direction of oligonucleotide theraputics, namely achieving the leap from "RNA therapy → standard treatment".

The success of Inclisiran has greatly stimulated capital and R&D enthusiasm. In the first half of 2025 alone, major positive news frequently emerged for nucleic acid drugs in the lipid-lowering field:

• In June, Eli Lilly's siRNA drugs Solbinsiran and Lepodisiran, published in The Lancet and *The New England Journal of Medicine respectively, demonstrated the potential to significantly reduce LDL-C and Lp(a) levels with just twice-yearly dosing. Simultaneously, Eli Lilly announced the acquisition of Verve Therapeutics for approximately $1.3 billion, gaining its in vivo base editing platform and pipeline, targeting key lipid-lowering targets including PCSK9, ANGPTL3, and Lp(a).
• In May, Ionis Pharmaceuticals announced positive topline results from the Phase III trial of its ASO therapy Olezarsen for the treatment of hypertriglyceridemia. It is expected to become the standard therapy for this indication.
• In March, CRISPR Therapeutics entered into a strategic collaboration with Jingyin Pharma totaling nearly $900 million to jointly develop the long-acting siRNA therapy SRSD107 for the prevention and treatment of thrombotic diseases.

These cases not only demonstrate the high level of attention nucleic acid drugs have garnered in the lipid-lowering track but also reflect the continuous breakthroughs in this field, including expanded indications, target diversification, and continuously reduced dosing frequency.

In April 2025, the self-developed Class I new drug DNV001 injection from Hangzhou Dingle Xinwei Biotechnology Co., Ltd. officially received clinical trial approval (Acceptance Number: CXHL2500095). DNV001 is a GalNAc-siRNA that knocks down PCSK9 mRNA in liver cells, blocking PCSK9 expression at the source. Pharmaceutical and preclinical studies indicate that DNV001 has excellent stability, safety, and efficacy, potentially achieving the goal of long-term lipid reduction with just two injections per year in the clinic.

Behind this innovative drug DNV001, Hongene, as an important partner for Dinglexinwei, provided end-to-end CDMO services, including:

1. Development of enzymatic processes required for nucleic acid raw material synthesis
2. Scale-up production of small nucleic acid Active Pharmaceutical Ingredient (API) and Drug Product (DP)
3. Sample analysis, pharmaceutical documentation writing, and regulatory submission support

Leveraging Hongene's stable enzymatic ligation synthesis technology platform, DNV001 was the first to achieve: (1) Ultra-high purity in clinical batch products; (2) Stable and controllable processes, simplifying subsequent process and analytical method development difficulties; (3) Highly stable scale-up production, significantly reducing production costs. Currently, DNV001 is also known to be a product among its peers that, under equivalent quality requirements, has a unit production cost low enough to meet the pricing standards of China's medical insurance.

In the same month, CSPC Pharmaceutical Group announced that its self-developed siRNA drug SYH2068 had received approval from the CDE to conduct clinical trials in China. This drug employs a strategy of optimized sequences and chemical modifications to achieve a more durable gene silencing effect, potentially enabling ultra-long-acting reduction of Lp(a).

In March, Sirius Therapeutics announced that its siRNA pipeline SRSD216 had received IND approvals in both China and the US. This drug can specifically modulate the LPA gene, reducing the production of Apo(a) in the liver and lowering circulating Lp(a) levels. Preclinical in vivo studies showed that a single administration reduced Lp(a) levels by almost 100%, with the effect lasting over 6 months.

As one of the earliest enterprises in China to strategically position itself in nucleic acid raw materials, Hongene has been deeply involved in the nucleic acid field for 27 years, committed to providing clients with excellent nucleic acid drug CDMO services.

Advantages of an Integrated Industrial Chain.
From core raw material supply to formulation development and production, truly providing clients with a "one-stop" solution.

Ultra-Large-Scale Production Base.
In January 2025, the company's commercial production base for oligonucleotide theraputics located in Fengxian, Shanghai, officially commenced operations. This production base covers 249 acres, complies with FDA, EMA, and NMPA regulatory requirements, and possesses the following core advantages:

1. High-Purity Synthesis: Equipped with multiple OligoPilot™ and OligoProcess™ 10-1800 mmol oligonucleotide synthesizers, advanced purification and detection systems, pioneering the achievement of a 98% high-purity small nucleic acid drug API production process.
2. "Ton-Level" Nucleic Acid API Production Capacity: Designed with 48 synthesis production lines, supporting 1800 mmol high-load synthesis, enabling seamless scale-up from laboratory scale to global commercial supply.
3. Diversified Formulation Service Platform: Includes lyophilized powder and liquid injection platforms, flexibly adapting to different clinical/commercial needs.
4. Digital Systems: Enabling audit transparency, efficient release, and complete data traceability.

The operation of this base marks a solid step forward for Hongene in the field of nucleic acid drug CDMO, allowing it to provide more satisfactory services to clients with enhanced capabilities.

Excellent Technology Platform.
Hongene's proprietary next-generation technology platforms, such as enzymatic ligation synthesis, lay a solid foundation for lower production costs and simplified development processes. When facing products like Inclisiran that have a "large patient population and high volume demand," it can provide more cost-effective and sustainably scalable manufacturing solutions, thereby better meeting the accessibility and pricing needs of the global market.

From the approval of Inclisiran as a monotherapy to various signals from the global nucleic acid industry, it is evident that nucleic acid drugs are no longer confined to niche diseases but are reshaping the landscape of chronic disease treatment.

In this transformation of the medical paradigm, Hongene, with its integrated supply chain capabilities, strategic investment in advanced processes, scalable global manufacturing facilities, and excellent one-stop nucleic acid drug CDMO platform, will become a solid force aiding the rapid development of the nucleic acid drug industry.