Small nucleic acid drugs have become the "dark horse" of the pharmaceutical industry.
In recent years, many global pharmaceutical giants such as Novartis, GSK, and Novo Nordisk have entered the small nucleic acid drug track through mergers and acquisitions, BD, etc., with a potential total amount of more than 20 billion US dollars.
At the beginning of 2024, two Chinese pharmaceutical companies have reached large deals with MNC to go overseas: first, Boehringer Ingelheim spent more than $2 billion to jointly develop small nucleic acid innovative therapies for the treatment of liver diseases with Ribo Biologics, and then Novartis spent $4.2 billion to introduce a variety of cardiovascular siRNA drugs from Bowang Pharmaceutical.
Today, the small nucleic acid drug track has entered the harvest period: there are nearly 20 small nucleic acid drugs that have been approved for marketing and are on sale in the world, and the total global sales in 2016 were only 100 million US dollars, and by 2023 they have soared to 4.32 billion US dollars.
And that's not the end of it. As more disease areas are approved, the market ceiling for small nucleic acid drugs will be higher.
01
Why does MNC bet so much?
要说MNC巨头进军小核酸药物赛道的经典案例,莫过于诺华豪掷97亿美元收购The Medicines Company,拿下了潜在"重磅炸弹"inclisiran。
In addition, GLP-1 weight loss drug giant Novo Nordisk also spent $3.3 billion to acquire Dicerna, a development company for RNA interference therapy; In July last year, Roche also spent $2.8 billion to introduce Zilebesiran, a hypertensive RNAi therapy, from Alnylam, a pioneer in the field of siRNAs.
Why does MNC bet heavily on small nucleic acid drugs?
As a new class of drugs that are different from small molecule chemical drugs and antibody drugs, small nucleic acid drugs have many inherent advantages, including: short R&D cycle (fast screening of drug targets), wider therapeutic field (rich targets), good safety (small dosage), and long-lasting effect (long half-life).
Especially with its long-term effect and wide range of therapeutic fields, small nucleic acid drugs are leading the outbreak of the third-generation drug revolution.
Because it is not limited by the druggability of the target, theoretically various diseases caused by the overexpression of specific genes can be treated by small nucleic acid drugs. This means that small nucleic acid drugs will not be limited to the field of rare diseases.
Although in the field of rare diseases, the "king of drugs" with cumulative sales of more than 10 billion US dollars has been born - Spinraza (nusinersen, nusinersen sodium) jointly developed by Ionis and Biogen (Biogen), with global sales of US$1.794 billion and US$1.741 billion in 2022 and 2023, respectively, this is not the end of small nucleic acid drugs.
After all, small nucleic acid drugs have a long half-life and can be calculated on a monthly basis, which can greatly improve patient compliance, which has great clinical value for the treatment of chronic diseases. The number of patients with chronic diseases is larger, and the market space is broader.
From a global perspective, the indications of small nucleic acid drugs are quite widely distributed: in addition to rare genetic diseases, they also cover multiple disease areas such as tumors, cardiovascular, digestive tract and metabolic diseases. If a breakthrough can be successful, the market size of small nucleic acid drugs will achieve explosive growth.
Global distribution of small nucleic acid drug clinical pipeline indications
Data source: Huajing Intelligence Network, Northeast Securities
Today, the application scope of small nucleic acid drugs has successfully expanded from rare diseases to chronic diseases.
Novartis' long-acting hypolipidemic therapy Inclisiran (Leqvio, Inksland) was approved by the European Union and FDA in 2020 and 2021 respectively for the treatment of adult hypercholesterolemia and mixed dyslipidemia, which proves the therapeutic potential of small nucleic acid drugs in the field of chronic diseases.
With the long-term advantage of only 2 injections per year, Inclisiran's sales soared from $12 million in 2021 to $355 million in 2023, and then increased to $151 million in the first quarter of this year at a 139% year-on-year growth rate. Novartis said that Inclisiran's ramp-up rate is basically the same as that of the heart failure blockbuster drug Entresto, which is Novartis' best-selling product, with sales exceeding $6 billion in 2023.
It can be seen that the market potential of small nucleic acid drugs is comparable to the "popular fried chicken" ADC track, which is naturally an excellent choice for MNC giants to enrich their next-generation product pipelines.
02
Milestone Breakthrough:
mRNA vaccines, chronic diseases
Small nucleic acid drugs are one of the branches of nucleic acid drugs, and others include mRNA vaccines and small molecule nucleoside similar drugs.
In recent years, nucleic acid drugs have achieved two major breakthroughs: first, mRNA vaccines have been approved for the first time to treat diseases other than the new crown, and second, small nucleic acid drugs have been successfully expanded to common chronic diseases.
On May 31 this year, Moderna announced that its mRNA vaccine mRNA-1345 was approved by the FDA for the protection of adults aged 60 and above from lower respiratory tract diseases caused by respiratory syncytial virus (RSV) infection, becoming the world's first mRNA RSV vaccine and the world's first non-COVID mRNA vaccine.
So far, three RSV vaccines have been approved for marketing in the world, in addition to mRNA-1345, there are GSK's Arexvy and Pfizer's Abrysvo, with sales of $1.53 billion and $890 million respectively in 2023.
Compared with the breakthrough of mRNA vaccines, the successful expansion of small nucleic acid drugs into the field of chronic diseases may be more of a milestone.
The approval of Novartis' new siRNA drug inclisiran has fully opened up the imagination of the market for the application of small nucleic acid drugs in a wider range of indications.
Not long ago, Silence Therapeutics also announced that its long-acting siRNA therapy zerlasiran achieved positive results of "more than 90% reduction in blood lipids" in a Phase II clinical trial, and was well tolerated with no serious safety concerns.
Roche's US$2.8 billion introduction of the AGT RNAi drug Zilebesiran from Alnylam is also a revolutionary drug in the field of chronic diseases, and is expected to become the world's first long-acting antihypertensive drug (one injection every six months). Alnylam expects Zilebesiran's peak sales potential to be well above $4 billion.
In addition to Roche, there are also many Chinese pharmaceutical companies that have deployed AGT RNAi drugs, including Innovent SGB-3908, Sirnaomics STP-136G, Ribo Biologics RBD-9079, etc., all of which are currently in the early clinical stage.
In addition to lowering lipids and blood pressure, the infinite possibilities of small nucleic acid drugs are also reflected in the disease fields that are expected to give birth to "big drugs", including tumors, NASH/MASH, neurological diseases, etc.
For example, Sirnaomics, China's "No. 1 RNAi therapeutics", has deployed two drug candidates for tumors, including STP705 and STP707.
Among them, STP705 is a dual inhibitor of TGF-ß1 and COX-2 that can be applied locally, which is in phase II clinical trials for basal cell carcinoma (BCC), and has been granted orphan drug designation for cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC); STP707 is a dual inhibitor of TGF-ß1 and COX-2 that is in clinical trials for the treatment of solid tumors and liver cancer.
In addition to laying out a variety of pipelines for rare diseases, well-known domestic small nucleic acid pharmaceutical companies Ribo Biotech and Bowang Pharmaceutical also involve cardiovascular and metabolic diseases.
Ribo's R&D pipeline
Image source: The company's official website
In the cardiovascular field, the RBD7022 for the treatment of hyperlipidemia developed by Ribo Biopharma has licensed the rights and interests of Chinese mainland, Hong Kong and Macau to Qilu Pharmaceutical in December last year, and is expected to obtain a total transaction value of 700 million yuan; In January this year, a number of cardiovascular siRNA drugs were awarded to Novartis for a total of up to US$4.2 billion.
In the field of metabolism, Ribo has laid out RBD4988 for the treatment of type 2 diabetes and RBD0066 for the treatment of gout; Bowang Pharmaceutical mainly has a variety of pipelines for the treatment of obesity and non-alcoholic steatohepatitis.
In addition, Bowang Pharmaceutical has also laid out 6 pipelines for neurological diseases, including Alzheimer's disease, Parkinson's disease and pain.
03
It is a trend of "three kingdoms".
Looking at the global market, Alnylam, Ionis, and Sarepta, which have been approved for a number of small nucleic acid drugs, show a trend of "three kingdoms" and carve up the global market share.
For example, Alnylam has almost monopolized the siRNA drug market, with the approval of Amvuttra, Leqvio (Inclisiran), Onpattro, Givlaari and Oxlumo, with sales of US$560 million, US$355 million, US$355 million, US$220 million and US$110 million in 2023, respectively, totaling US$1.6 billion, accounting for nearly 40% of the global market share of small nucleic acid drugs.
Ionis and Sarepta mainly occupy the ASO drug market, among which Spinraza (nusinersen, nusinersen sodium), jointly developed by Ionis and Biogen, will have sales of US$1.741 billion in 2023, still occupying the throne of the global "drug king" of small nucleic acid drugs; Eteplirsen, developed by Sarepta, has sales of $541 million in 2023.
Global sales of small nucleic acid drugs in 2023 (US$ 100 million)
Image source: Compiled by Xingyao Research Institute
It is worth mentioning that Alnylam and ION also ushered in a number of milestones this year, involving indications including hypertension, Alzheimer's disease, hepatocellular carcinoma, hemophilia, MASH and IgA nephropathy.
Among them, Zilebesiran, an ultra-long-acting antihypertensive drug developed by Alnylam, has published the results of a phase II clinical trial for the treatment of hypertension in JAMA in February this year: all patients in the Zilebesiran group decreased their systolic blood pressure after 3 months of treatment, and the 24-hour average systolic blood pressure of patients receiving 300mg and 600mg doses of Zilebesiran decreased by ≥15mmHg. The reduction in systolic blood pressure was maintained up to 6 months. Moreover, the safety and tolerability were also good, and the incidence of adverse events was low.
In other words, subcutaneous injection of Zilebesiran, 1 injection can be administered for half a year, compared to taking antihypertensive drugs twice a day, which greatly improves compliance.
Small nucleic acid drug pipeline milestones to watch in 2024
Source: The company's official website, Industrial Securities Research Report
In addition, the Phase II clinical trial of ION224, an ASO therapy developed by Ionis, for the treatment of MASH, achieved positive results: the primary endpoint was met at both doses (120 mg and 90 mg), liver histological improvement was achieved, and an important secondary endpoint of MASH resolution was also met.
MASH is a well-known R&D black hole in the pharmaceutical industry, but due to the broad market prospects, many pharmaceutical companies are still eager to try it. According to Frost & Sullivan, the global MASH drug market is expected to reach $10.7 billion in 2025 and grow to $32.2 billion by 2030.
In addition to rare genetic diseases and cardiovascular, MASH is also a key disease field for small nucleic acid drugs. Which pharmaceutical company can take the lead in winning the first kill?
04
epilogue
At this stage, long-acting drugs are in full swing, and various long-acting therapies have repeatedly achieved good results in clinical trials, which continue to stimulate the enthusiasm of capital and pharmaceutical companies.
From the success of the phase III clinical trial of long-acting olanzapine for the treatment of schizophrenia, to the amazing results of Gilead's long-acting HIV therapy Lenacapavir, long-acting drugs have become the new favorite in the pharmaceutical field.
It is worth mentioning that small nucleic acid drugs with long-term advantages are gradually emerging. The outstanding performance of MNC giants such as Novartis and Roche in siRNA therapeutics highlights the important position of small nucleic acid drugs in the field of long-acting drugs.
It is not difficult to foresee that small nucleic acid drugs are likely to be the birthplace of "big drugs".
Resources:
1. Financial reports, announcements, and official micro-accounts of each company
2. "20240221-Lianlong-300596-Anti-aging Agent Leading Enterprise, Diversified Development to Build a Fine Chemical Platform", Northeast Securities
3. "2023 Global Top 10 Small Nucleic Acid Drug Sales List Released, with a total amount of 4.32 billion US dollars!" , Star Shine Research Institute, 2024-03-12
4. SDIC Securities, Industrial Securities Research Report