Liang Zicai: Small Nucleic Acid Therapeutics Poised to Drive the 'Third Wave' of Modern Pharmaceutical Innovation

At the invitation of the organizers, Professor Liang Zicai, Founder, Chairman and CEO of Suzhou Ribo Life Science, delivered a presentation titled “Advancing Small Nucleic Acid Drugs to Clinical Trial Stage in China” at the “2020 Shenzhen International Biopharmaceutical Industry Innovation and Development Conference.” This article is compiled based on the content of the presentation and has been confirmed by the speaker.

Professor Liang Zicai Delivers a Presentation Onsite

01

Oligonucleotide Therapeutics Face a Major Strategic Window of Opportunity

Two recent news stories have been groundbreaking, sparking industry interest in small nucleic acid drugs.

News item one: Novartis injects nearly $10 billion to acquire The Medicines Company. News item two: BlackRock Group makes a $2 billion major investment in Alnylam.

Both news items are related to Inclisiran, a small interfering RNA (siRNA) drug used for lipid-lowering therapy. The interval between the first and second doses is three months, followed by dosing intervals of up to six months for subsequent administrations. This ultra-long-acting medication holds potentially disruptive significance in the field of lipid management and even in the broader realm of chronic disease treatment.

Oligonucleotide drugs mainly fall into two categories: siRNA and antisense oligonucleotides. Both small molecules and antibodies act at the protein level. In contrast, the mechanisms of action of these two classes of oligonucleotide drugs differ from those of small molecules and antibodies; they do not target proteins but instead act at the level of mRNA, the assembly line for protein synthesis.

Since the founding of Ionis, the antisense oligonucleotide R&D company, in 1987, small nucleic acid drugs have undergone a 30-year long march. Over these three decades, small nucleic acid therapeutics have experienced numerous life-and-death challenges, emerging from the ashes to achieve their current promising outlook. To date, seven antisense oligonucleotide drugs and three siRNA drugs have been approved.

The development of oligonucleotide therapeutics as a pharmaceutical platform technology shares many similarities with the evolution of the antibody industry. Many have witnessed the rise of antibody drugs from their inception in 2001 to their current prominence, and in recent years, numerous individuals have entered this field.

If small nucleic acid drugs are benchmarked against the development trajectory of antibody drugs, the current assessment is that they are at the industrial development level of antibody drugs in 2001 (indicated by the red circle): key technologies have been breakthrough, and blockbuster products are beginning to emerge, with the industry on the verge of an explosive growth period.

Given the numerous advantages of small nucleic acid drugs, they are likely to catch up and surpass others in the next decade, forming a market worth tens of billions of dollars. This is why small nucleic acid drugs have become a highly contested area in the global pharmaceutical industry.

Small nucleic acid drugs represent the most likely breakthrough for China to establish a localized advantage in innovative pharmaceuticals. Whether this breakthrough can be achieved depends on our collective efforts.

The landscape of innovative drugs has evolved from an era dominated solely by small molecules to the present day, where small molecules and antibodies each account for half of the top ten best-selling drugs. It is projected that after another decade or so of development, the innovative drug landscape may shift to a tripartite structure comprising small molecules, antibodies, and small nucleic acids. Small nucleic acid therapeutics are poised to trigger the third wave in modern pharmaceuticals.

02

Oligonucleotide Therapeutics: The Third Wave of Modern Pharmaceuticals

Why Have Small Nucleic Acid Drugs Become the Third Wave of Modern Pharmaceutical Development? Because small nucleic acid drugs possess many advantages that small-molecule drugs and antibody drugs do not. First, the broad range of targets for small nucleic acid drugs gives them enormous potential. Currently, more than 2,000 target genes are known, but only 400–500 of them are truly druggable.

As for small nucleic acids, since they act at the mRNA level, and the mRNAs of different target genes are very similar in their susceptibility to targeting despite differences in sequence, small nucleic acid drugs have a rich array of targets and can treat a broad spectrum of diseases. Secondly, the mechanism of small nucleic acid drugs is groundbreaking. These drugs will make many previously untreatable diseases treatable, transitioning treatments from short-acting to long-acting and even ultra-long-acting formulations.

As previously mentioned, inclisiran is administered via injection once every six months, yet this does not represent the longest duration of efficacy achievable with small nucleic acid drugs. From a technical perspective, annual dosing is highly feasible. This advancement would usher in a revolutionary shift in the management models for chronic diseases. Furthermore, small nucleic acid therapeutics offer the advantage of digital design.

The digital design of small nucleic acid drugs is a significant advantage that makes them superior to any previous drug development. This enables the research and development of small nucleic acid drugs to be much faster than that of other types of drugs.

Meanwhile, a frequently overlooked advantage is the robust foundation in oligonucleotide drug development and translational medicine, which is unmatched by any other class of therapeutics. The application of RNA interference technology has become widespread, with minimal differences between laboratory research methods and clinical practices. Once delivery is achieved, the translation from bench to bedside is relatively straightforward.

This will ensure that oligonucleotide drugs can emerge as a leading force. Due to these unique advantages, oligonucleotide drugs are poised to become the third wave of therapeutics, following small-molecule and antibody drugs.

The field of oligonucleotide therapeutics has surpassed the tipping point for explosive growth and is now entering a phase of rapid development. Four signals indicate that oligonucleotide therapeutics are entering this rapid development phase:

The Emergence of Blockbuster Drugs (Spinraza Surpasses $2 Billion);

The emergence of key technologies supporting the development of the entire industry sector (GalNAc delivery technology);

Multiple drugs submitted for approval in batches;

Major international pharmaceutical companies are generally involved (Novartis, AstraZeneca, Johnson & Johnson, Roche, Pfizer, Eli Lilly, Bayer, Biogen, Amgen, etc.).

03

Current Status of Oligonucleotide Drug Development in China

The global landscape: It has been exactly 33 years since the emergence of Ionis in 1987. Currently, approximately seven antisense oligonucleotides and three siRNAs have been approved.

China’s initial oligonucleotide pharmaceutical industry began in 1998, but Ribo Life Science is one of the earliest oligonucleotide drug development companies that remains active today. Ribo Life Science was established in 2007, followed by Suzhou Sinotech, and over the next decade, a number of oligonucleotide companies such as Zhongmei Ruikang were founded. Currently, there are eight oligonucleotide products in China undergoing clinical trials at various stages.

China's oligonucleotide pharmaceutical industry started later than abroad, but we are catching up quickly. Current status of China's oligonucleotide pharmaceutical industry:

Leading enterprises are beginning to emerge (small nucleic acid pharmaceuticals—Ribo Life Science, Sinotech; small nucleic acid active pharmaceutical ingredients—Genomed, Ribo Life Science, WuXi STA, Asymchem).

Running neck-and-neck with the world's advanced technologies in several areas (such as the "delivery systems" of Ribo Life Science and Sinopep);

A pipeline of oligonucleotide therapeutics is currently in various stages of clinical trials and preclinical development. However, to date, the participation of large Chinese pharmaceutical companies in the oligonucleotide field has been virtually nonexistent.

04

Ribo Life Science—A Leading Enterprise in China's Oligonucleotide Industry

Ribo Life Science, founded in 2007, has established internationally leading R&D capabilities for oligonucleotide therapies, a comprehensive oligonucleotide drug development platform, and the largest oligonucleotide drug pipeline in Asia. It was the first company in Asia to achieve a breakthrough in GalNAc delivery technology.

Ribo Life Science has achieved multiple breakthroughs, marking the first instances of their kind in China’s small nucleic acid drug development. Currently, one product has entered Phase III clinical trials, two products are in Phase II clinical trials, and several candidates are scheduled to submit clinical trial applications within the next 12 to 18 months.

Ribo Life Science boasts a broad spectrum of indications, primarily determined by the characteristics of small nucleic acids. As a technology platform, small nucleic acids are applicable to a variety of indications, including ocular diseases, metabolic disorders, and tumors. The three key therapeutic areas focused on by Ribo Life Science’s R&D efforts include viral diseases, metabolic disorders, and hematological diseases.

A Brief Introduction to Three Small Nucleic Acid Drugs Developed by Ribo Life Science:

The first candidate is a small nucleic acid drug targeting PCSK9 for the treatment of hyperlipidemia. A single subcutaneous injection at a dose of 9 mg/kg body weight can reduce low-density lipoprotein cholesterol (LDL-C), with effects lasting up to 100 days. This data reflects a single-dose regimen; with multiple dosing, an ultra-long-acting profile allowing for supplemental doses every six months should be achievable.

The second drug: Given the high prevalence of hypertriglyceridemia in the Chinese population, we have developed a small nucleic acid drug to lower triglyceride levels. As shown, a dose of 0.3 mg/kg body weight already achieves significant triglyceride reduction, but with limited durability. At doses of 1 mg/kg and 3 mg/kg body weight, the duration of effect is extended to 80 days and 120 days, respectively. The small nucleic acid drug demonstrates an excellent safety profile; toxicology studies have been conducted at doses up to hundreds of mg/kg body weight, showing very good tolerability. It is anticipated that even longer durations of action can be achieved.

The third drug is a small interfering RNA (siRNA) therapeutic targeting the hepatitis B virus. Developed by Ribo Life Science over nearly a decade, it has recently demonstrated promising efficacy. Following administrations on Day 0, Day 7, and Day 14, with no further dosing thereafter, the drug completely suppressed hepatitis B surface antigen (HBsAg) for up to seven months. Although numerous small-molecule drugs are available for hepatitis B treatment that effectively suppress HBV DNA, there are currently no marketed agents capable of inhibiting HBsAg. This lack of HBsAg suppression is the primary reason why hepatitis B remains incurable.

In animal studies, our small nucleic acid drug not only achieved sustained suppression of the surface antigen, but also induced surface antibody responses in 60% of the animals. The emergence of surface antibodies signifies an active immune defense against HBV, which is the most critical marker for achieving a functional cure. As China bears a high burden of hepatitis B, achieving a functional cure for HBV will yield not only economic benefits but also substantial social impact. We seek to collaborate with pharmaceutical companies specializing in HBV therapeutics to jointly realize this goal.

05

Summary

As a novel biopharmaceutical technology platform, oligonucleotide therapeutics have now reached maturity and are poised for rapid development. They have already demonstrated characteristics of disruptive technologies, particularly in their potential to transform the treatment paradigms and strategies for chronic diseases.

This shift will bring about a monoclonal antibody-style restructuring of the pharmaceutical industry landscape. The next ten to twenty years represent a critical window of opportunity for the development of the nucleic acid therapeutics industry. We look forward to collaborating with all stakeholders to jointly create a brilliant future for China’s small nucleic acid drug industry!

Responsible Editor: Lulu Jun

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