Ribo Bio Secures Landmark BD Deals with Qilu Pharma and Boehringer Ingelheim, Signaling Small Nucleic Acid Therapeutics’ Rise Beyond ADCs

"In the small nucleic acid (RNAi) therapy field, truly astonishing large BD deals have yet to come."

It is not surprising that ADC has delivered the first big gift of the year. What is more surprising is that China's small nucleic acid drug field has finally ushered in the first large-scale transaction with a multinational pharmaceutical company.

A small nucleic acid Biotech named Ribo Life Science has reached a multi-target cooperation exceeding 2 billion US dollars with Boehringer Ingelheim (BI).The transaction amount exceeded the first BD of ADC at the beginning of the year.The collaboration between the two aims to achieve a significant milestone: the development of an NASH siRNA drug. Just days before partnering with BI, Ribo Life Science had granted Qilu the rights for the development, production, and commercialization in China of its new PCSK9 small nucleic acid drug.

A close look at the two partners in quick succession,One is a traditional large pharmaceutical company, corresponding to the star target of lipid-lowering drugs; the other is a top 20 revenue-generating MNC, set to jointly tackle a disease area that has been a headache for many MNCs.Ribo Life Science couldn't have achieved this without real capability.

When the first collaboration between a small nucleic acid company in China and an MNC was announced, Ian Yin, the founder of 3E Bioventures Capital who has been following the small nucleic acid field since obtaining his Ph.D. and witnessed the industry’s ups and downs, felt quite emotional. In 2018, the global launch of the small nucleic acid drug Onpattro confirmed the clinical application of LNP delivery technology, providing real momentum for the entire nucleic acid industry. However, what followed was the COVID-19 pandemic, during which the prominence of mRNA technology overshadowed small nucleic acids."If it weren't for the pandemic, small nucleic acid drugs would have received more attention compared to mRNA."

The approval of Novartis' PCSK9 small nucleic acid drug in China in 2023, the breakthrough $2 billion sales of Spinraza for the treatment of the rare disease SMA, and the recent collaborations on small nucleic acid drugs between Yangtze River Pharmaceutical and Ribo Life Science, as well as between Innovent and Saint-Gene Biotech, all signal to the industry: this field has reached a critical tipping point.

In the view of another investor, Liang Yu, the truly astonishing large-scale BD deals in this field have yet to come."The nucleic acid industry is hot now, but it hasn't reached its peak yet.""When small nucleic acid BD deals come one after another, don't be surprised."

An industry insider once lamented to E Pharmacy Manager that the research and development of small nucleic acid drugs in China seemed to be thriving, but sometimes it just touched the edge of prosperity, lacking a breakthrough milestone to stimulate. Broadening the perspective, he saw that small RNA molecule drugs in the United States were already booming, but most domestic companies still focused their research on mRNA.

Ribo Life Science's collaboration exceeding $2 billion finally brings a powerful "stimulant." However, it has taken many years for the few small nucleic acid drug companies in China to reach this point.

Compared with many peers and the "latecomers" who have jumped on the bandwagon, Ribo Life Science was established very early. From its founding in 2007 to being widely recognized today, it has taken nearly 20 years. It took eight years for its first small nucleic acid drug to gain clinical trial approval; in its tenth year, Ribo Life Science reached a cooperation with Ionis, one of the world's top three small nucleic acid drug giants, introducing several of its products, including SR062, China's first small nucleic acid drug for treating type 2 diabetes.Relatively speaking, Ribo Life Science's independent research and development capabilities are not particularly prominent in the industry, and it mainly focused on authorized introductions in the early days.

But the most valued aspect of small nucleic acid drug companies lies in their technology platforms. Looking at the nucleic acid drug field, investors generally place more emphasis on the validation of the overall technology platform rather than focusing on one or two specific products. Some investors have told E Pharma Manager that investments by investment institutions in a single small nucleic acid drug might "go down the drain," but as long as the platform remains, the company's advantages can be sustained in the future.

Global small nucleic acid giants have also undergone a long and agonizing process of building platforms. Before Alnylam achieved a high platform conversion rate of one new drug launched per year on average, it had endured 16 years of "cold bench" with no new drugs reaching the market during this period.

Ribo Life Science was favored by BI not because it took a "niche path," but because it laid a solid foundation in popular research and development fields. It built its own RIBO-GalSTAR technology platform, which has earned it positive expectations.

The GalNAc small nucleic acid drug delivery system used in RIBO-GalSTAR technology, which is favored by most companies in and outside of China, serves as the most mainstream supporting platform globally. The application of this technology has led to the approval of new products, particularly for small nucleic acid drugs targeting liver-related chronic diseases.

However, the difference lies in that RIBO-GalSTAR can specifically target pathogenic genes in hepatocytes, selectively inhibit their mRNA, thereby developing small nucleic acid therapies, which are expected to target undruggable targets by traditional drug molecules, achieving BI's goal of developing drugs in the field of liver diseases.

RIBO-GalSTAR is a small nucleic acid liver-targeted delivery technology independently developed by Ribo Life Science over many years. It has now established a strong patent protection barrier, obtained patent approvals from key jurisdictions such as China and the United States, and has been applied in the development of various liver-targeted nucleic acid drugs, featuring highly specific liver targeting, high efficiency, and long-lasting effects with international competitive standards.

Six of the seven key products under development by Ribo Life Science are based on this technology platform.The collaboration between this Biotech and Qilu on RBD7022, a GalNAc-conjugated siRNA drug for treating hyperlipidemia, is a recognition of the capabilities of the RIBO-GalSTAR technology platform. Existing research data show that RBD7022 has good safety and tolerability with significant lipid-lowering effects. It has the potential to achieve dosing intervals of several months or even longer, greatly improving patient compliance. This product will help Qilu build more competitiveness in the treatment of chronic diseases, including cardiovascular conditions.

Notably, in line with the international frontier of small nucleic acid technology innovation, Ribo Life Science has established an independent and controllable small nucleic acid drug research and development platform that integrates the entire technology chain, covering the full life cycle from early research to industrialization, which is its undeniable advantage.

In addition to building platforms and laying foundations, another thing Ribo Life Science did right was reshaping a new "Golden Triangle" when the industry truly began to take off.

It is often said that good capital, good varieties and projects, and a good team form the "golden triangle" of a company's success. In 2022, Alnylam drove the small nucleic acid track to gradually enter the spotlight, with its three nucleic acid drugs for rare diseases achieving over 35% high growth. The entire track has quietly attracted more MNCs, traditional large pharmaceutical companies, and innovative pharmaceutical enterprises.

Ribo Life Science realized that this was a critical stage on the verge of a breakthrough, so it accelerated the progress of multiple clinical trials both in China and internationally. It also established an international R&D center, Ribocure Pharmaceuticals AB, in Sweden, and secured $40 million in Series E1 financing in the same year. More importantly, the company welcomed Dr. Liming Gan as the new Global Head of R&D and Chief Medical Officer (CMO), who also took on the role of CEO for Ribo Life Science's first overseas (Sweden) R&D center.

Gan Liming has led several major collaborations in AstraZeneca's nucleic acid drug field, while also participating in and leading the development of various non-small molecule drugs, including peptides, antibodies, ASO, cell therapy, and mRNA. In 2016, he led the world's first mRNA patient trial and has long served as the global clinical development leader for cardiovascular, renal, and metabolic diseases at AstraZeneca.

As a result, in 2022, Ribo Life ScienceSweden R&D CenterHigh efficiency, advancing 3 projects to the clinical stage, with an average time from concept to implementation of 20-24 months.

First, it is important to clarify that small nucleic acids and mRNA are actually two major categories of nucleic acid drugs. In a broad sense, small nucleic acids include siRNA, ASO, miRNA, saRNA, and nucleic acid aptamers, among others. Although the COVID-19 vaccine once sparked an investment and financing boom for mRNA, as the pandemic has cooled down, small nucleic acids, with advantages such as low cost and short development cycles, have once again returned to the "top spot."

In fact, several insiders told E Pharmacy Manager,2024 will not only continue the intense trend of 2023, but the small nucleic acid field is also highly likely to see some large-scale mergers and acquisitions or BD transactions.

In recent years, the small nucleic acid field has not only attracted strong entries from large MNCs such as Novo Nordisk, Novartis, and Roche, but also seen a rise in BD transactions from China as Chinese Biotech companies in the small nucleic acid sector achieve breakthroughs.

Roche and Novartis can be regarded as the two most active MNCs in the small nucleic acid field in 2023. In August, Novartis announced a collaboration with "pioneer" company Ionis Pharmaceuticals to develop new drugs in the cardiovascular disease (CVD) field driven by lipoprotein(a) — Lp(a). Then, in September, Novartis acquired DTx Pharma, a startup RNA therapy company, for $1 billion, gaining the latter's Fatty Acid Ligand Conjugated Oligonucleotide (FALCON) platform in the delivery field.

Roche drove the largest BD deal in the small nucleic acid field in 2023.In July, Roche announced a collaboration with Alnylam to co-commercialize Alnylam's investigational RNAi therapy zilebesiran, with a total deal value exceeding $2.8 billion.

The火热 trend of MNCs in the small nucleic acid field also "spread" to China in 2023.In addition to the two BD collaborations of Ribo Life Science mentioned above, Innovent and Saint Biologics also reached a collaboration at the end of December to jointly develop the siRNA candidate drug SGB-3908 targeting angiotensinogen (AGT) for the treatment of hypertension; RiboComm Therapeutics also partnered with Yangtze River Pharmaceutical, focusing on the research and development of small nucleic acid innovative drugs.

Notably, in the current market downturn, investment and financing in the small nucleic acid sector are making a remarkable breakthrough against the trend. Public data shows that in 2023, there were nearly 80 financing events in the nucleic acid drug field globally, totaling over $2 billion. More than half of these were early-stage financings (Series A or earlier), with an amount exceeding $1 billion, representing a 24% increase compared to 2022. In China, financing in nucleic acid drugs has emerged exceptionally strong, with 33 companies securing funding, totaling nearly 5 billion yuan. Among them, Genexine Biologics topped the list by raising $80 million in its Series A+ round.

In fact, the world's earliest small nucleic acid drugs were already on the market around 2000. Currently, 16 small nucleic acid drugs have been approved for marketing. China's "first generation of nucleic acids," Ribo Life Science, was also established as early as 2007.So, why did this wave of intensive BD and M&A only reach the small nucleic acid field in 2023?

Multiple industry insiders told E Pharmacy Manager that on the one hand, the expansion in the field of indications has been further validated, and on the other hand, the commercial achievements of small nucleic acid drugs have been recognized.

For example, in August 2023, Novartis' long-acting lipid-lowering siRNA cholesterol-reducing drug, inclisiran sodium injection (Inclisiran), was approved for marketing in China. As the world's only siRNA therapy for reducing low-density lipoprotein cholesterol (LDL-C), it requires only two injections per year to lower LDL-C. The commercial success of this product has been strongly demonstrated; according to Novartis’ financial report, the full-year sales of inclisiran sodium reached $112 million in 2022, and in the first half of 2023 alone, it hit $142 million, surpassing the total of the previous year.

At the same time, the research and development progress of inclisiran sodium in fields such as NASH, hepatitis B, and blood pressure reduction is also proving that the indications for small nucleic acid drugs are not limited to rare disease areas. Small nucleic acid drugs are believed to achieve breakthroughs with lower costs, longer efficacy, and even functional cures in these fields.

In addition, Yin Zheng also told E Drug Manager,In the traditional large molecule and small molecule fields, the clinical success rate of new drug development is often only about 10%, whereas Alnylam, the "pioneer" of small nucleic acid drugs, has a success rate of approximately 60% from Phase I to Phase III.

Back in China, the expansion of indications and the proof of commercial success are still indirect factors. The most direct reason comes from the progress made by leading small nucleic acid companies in China, which eventually attracted the favor of large companies.

In addition to Ribo Life Science entering the "fast lane," clinical progress has also been made in the pipelines of Sirnaomics' STP705, Junshi Biosciences' JS401, and Rgenta Therapeutics' RAG-01.

For example, Sirnaomics' STP705 is an siRNA therapeutic drug. In the Phase II clinical trial of STP705 for the treatment of basal cell carcinoma (BCC) in 2022, the cohort receiving the 180μg dose level achieved 100% complete response (CR).

In addition, it can also be seen that some small nucleic acid Biotech startups in China are achieving technological breakthroughs. For example, Antishengshi, founded in 2017, whose founder Hua Yimin is the primary inventor of the SMA drug Nusinersen. The company is also the first in China to target RNA splicing and RNA editing in the development of antisense oligonucleotide (ASO) drugs.

However,In terms of R&D progress, China's small nucleic acid drugs are still in the early stage, and breakthroughs in technologies such as delivery systems and chemical modifications remain limited.An industry insider told E Pharm Manager that although the pipeline for liver-targeting in China has become quite abundant and is advancing rapidly, new technologies such as novel chemical modifications and extrahepatic delivery have not been widely explored by domestic companies. Currently, there is still insufficient understanding of the transport process of siRNA drugs inside and outside cells, as well as the binding details between siRNA and Ago proteins. These aspects could provide important guidance for chemical modification and delivery technologies.

However, for those Biotech companies with faster progress, we can expect larger and more intensive deals in the future. Yin Zheng stated, "The BD deal cycle with large companies usually takes 9-12 months. At the JPM conference, we may see bigger deals disclosed, which would indicate that China's small nucleic acid sector can secure a place on the global stage."

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