Merhado's $ 3.65 billion bet, Geely, BMS layout, TOP pharmaceutical company gold rush "alternative" RNA technology

Meridodon announced yesterday (August 16) that it reached a transaction with ORNA Therapeutics, an RNA therapy company, with a total amount of US $ 3.65 billion in cooperation agreements to discover, develop and commercialize multiple projects, including vaccines and vaccines in the field of infectious diseases and oncology. therapy.

This is another move to explore RNA drugs in depth.

This cooperation also means that Meridon has bypassed the linear RNA technology commonly used in MRNA technology, and instead adopts an update technology -ring RNA (Circular RNA, abbreviated as CirCRNA) to explore the future of RNA technology in the pharmaceutical field potential.

Companies such as circular biological, circular biology, Cirruma, Korite, and Ao Ming gene have set up a layout of ring -shaped RNA, which are currently in the financing stage.

In this transaction, Merhado will pay $ 150 million in prepaid to ORNA. ORNA may get up to $ 3.5 billion in development, supervision and sales milestones related to the progress of multiple vaccines and treatment plans, as well as any approved products in the transaction. Charming fees.

The two companies will jointly develop "multiple" projects and commercialize them, including vaccines and therapies for infectious diseases and cancer. ORNA will retain the rights of its ORNA-LNP technology platform and will continue to promote other wholly-owned projects in the fields of oncology and genetic diseases.

Meridon also invested $ 100 million in $ 221 million in Series B, which was completed on August 15.

ORNA completed $ 80 million in Series A financing in 2021. There are many top -level pharmaceutical companies in investors, including Geely's Kite, Beltime Schimibao (BMS), Astellas Venture Management and Novartis Biomedical Research Institute.

01

Many top pharmaceutical companies open RNA technology "gold rush"

In the new crown vaccine competition, the strong contrast attracts attention:

Pfizer and two small biotechnology companies won the competition.

And most of the world's largest and oldest vaccine manufacturers either wait too long or choose older technologies that are older and final.

Subsequently, top pharmaceutical companies opened a small -scale gold gold rush on RNA technology.

In 2021, GSK expanded the cooperation with CureVac, one of the first MRNA startups; Sanofi announced that it had acquired its MRNA partner Translate Bio for $ 3.2 billion.

Now, Merck has also revealed his strategy -cooperating with ORNA to develop its proprietary ring RNA.

In fact, Merhadon has been studying RNA for many years, but has not yet made breakthrough products.

In 2006, Meridodon acquired Sirna Therapeutics for $ 1.1 billion. The company developed RNA interference drugs (SiRNA) is now the world's leading SIRNA company Alnylam. But Meridon sold SiRNA's remaining assets 8 years later to ALNYLAM at a small part of the initial acquisition price.

Meridas and MRNA Pharmaceutical "Star" Moderna has a long -term cooperative relationship.

The two companies reached cooperation as early as 2018 to jointly develop two MRNA cancer vaccines-MRNA-5671 for Cancer vaccine against KRAS gene mutations, and personalized tumor vaccine MRNA-4157.

However, in February 2022, Meridodon announced the abandonment of cancer MRNA vaccine developed against KRAS gene mutations in cooperation with Moderna. Moderna announced that it has re-obtained the ownership of the cancer vaccine of the CAS for KRAS.

The cooperation between the two MRNA-4157 for personalized cancer vaccines is still underway. This vaccine can encode up to 34 new tumor new antigens. The results of the II phase II clinical trial of the project will be announced at the end of this year.

*At present, Moderna has a total of three cancer vaccine R & D pipelines, namely personalized tumor vaccines, KRAS vaccines developed in cooperation with Meridodon, and immunochemical check -in vaccines developed by themselves.

Meridon also invested in other RNA projects separately. For example, in July 2019, it reached a R & D cooperation agreement with Skyhawk Therapeutics. Skyhawk will use its SKYSTAR technology platform to help Merruston develop innovative small molecules that targeted RNA splits as potential methods for treating certain neuropathy and cancer.

Cooperation with ORNA is the other direction of Merck's layout RNA drugs.

02

Circle RNA, is the next -generation RNA technology?

What is special about ring RNA technology?

At present, in MRNA therapy, linear mRNA is the first choice, but its disadvantages are also obvious. A large amount of modification must be performed during synthesis to resist the degradation of cellular nucleic acid enzymes and avoid congenital immune stimulation, and then deliver it through lipid nanoparticles (LNP), the entire production efficiency is low and expensive. Moreover, even so, the half -life of the modified linear MRNA is still short, which greatly limits its therapeutic protein yield.

Circle RNA (CIRCRNA) is a natural RNA that naturally exists in mammalian cells. They are generated through different editing methods of the RNA. Scientists have found that the IRS sequence is responsible for starting protein synthesis in a virus RNA in the ring RNA, which can combine the ring RNA with the ribosomes to start protein synthesis. The ring -shaped RNA can resist the degradation of the cellular nucleus due to its first -end connection. Therefore, it is more stable and the immunogenic is lower. It has become a good alternative to linear mRNA.

▲ ORNA's ring RNA synthesis method (Source: ORNA company official website)

The circular RNA therapy originated from a paper published by the Daneil ADerson team of MIT (MIT) in 2018 in the Nature Communications journal. Based on its research, Daneil Aderson et al. Founded ORNA Therapeutics in 2019, becoming the first company in the world to develop new therapy for ring -shaped RNA.

ORNA Therapeutics's internal pipeline's main attack direction is to use the stability of the ring RNA to introduce the ring RNA of an expression antibody chimeric (CAR) in T cells, and directly generate CAR-T cell therapy in the human body to avoid from the patient from the patient The in vivo isolation cells and the tedious process of engineering transformation in vitro.

▲ ORNA's pipeline

In May 2022, data released by ORNA showed that the five -dose anti -CD19 ISCAR can completely clear the tumor in the heterogeneous transplantation model of acute lymphocyte leukemia mice. ORNA also released the treatment effect of LNP's micro -malnutrients encoded by CirCRNA coded in Du's muscle malnutrition (DMD) mice model.

ORNA therapeutics stated on its official website that the ring RNA, as a new RNA drug, can give full play to the potential of RNA and is expected to change the way of treating diseases. This technology has extensive application potential in various fields such as cancer, regeneration medicine, protein substitution, infectious diseases, and autoimmune diseases. By combining with the new delivery technology, it is expected to start the next breakthrough of RNA treatment.

In addition to ORNA Therapeutics, the ring RNA R & D company also has Laronde and Chimerna therapeutics.

Laronde was founded by the famous venture capital institution Flagship Pioneering in 2021. Laronde said the company's modular ring RNA design allows it to replace the genetically modified module that needs to be expressed to let the ring RNA express any type of protein. The company's goal is to develop 100 RNA drugs within 10 years.

In August 2021, Laronde announced the completion of a Series B financing with an amount of US $ 440 million.

Chimerna therapeutics uses the stability of the ring RNA from another angle. The company's innovative therapy is a type of ring -shaped RNA -based and combined with protein. The stability of the ring RNA makes the RNA appropriate body is expected to achieve the concentration of the treatment effect in the cell.

Companies such as circular biological, circular creatures, circular biology, Korite, and Ao Ming gene have set up a layout of ring -shaped RNAs and received widespread attention. Circular organisms and circular creatures were financed last year.

In November 2021, Yuanyin announced the completion of exceeding 100 million yuan Pre-A round of financing, which will focus on the use of circular RNA technology to develop vaccines and new therapies.

In December 2021, the ring code organism announced the completion of more than 20 million US dollars of Pre-A round financing. This is the second round of financing that the company has completed less than four months after the angel round financing in July 2021.

In May 2022, Suzhou Kori Midd Bio published a circular MRNA vaccine thesis on the pre-printing platform BiorXiv, using a new type of biodegradable AX4-LNP circular MRNA vaccine, which can induce strong immune response, and More temperature stability.

In July 2022, the Department of Pharmacy and Oming Gene in China Construction Circle RNA Pharmaceutical Research Institute.

03

In addition to the ring RNA, what other RNA is popular?

Based on RNA -based targeting drugs, it is expected to become the third wave of modern new drugs after small molecular drugs and antibody drugs. The RNA targeted drugs are started by mergers and acquisitions or joint development.

RNA targeted drugs mainly include antonym oligonucleotide (ASOS), small interference RNA (SIRNA), tiny RNA (MiRNA), messenger RNA (mRNA), RNA adaptation (Aptamer), short activation RNA (SARNA), RNA (SGRNA for CRISPR/CAS9 system), as well as small molecular drugs targeted by RNA.

At present, in addition to the highly anticipated MRNA vaccine, as well as the ring -shaped RNA introduced earlier, the antiserial oligonucleotide (ASOS) and small interference RNA (SIRNA) are the main forms of RNA targeted drugs developed in the clinic.

ASOS: A total of 9 models were approved, and IONIS and Sarepta accounted for the majority

ASOS (ASOS) is the RNA targeted drug with the largest number of listing markets.

It is a short single -chain oligonucleotide molecule (about 18 ~ 30NT), which can be based on a hybrid single -chain of DNA, RNA or DNA and RNA. (RNASE H1) causes degradation of mRNA under the action of RNASE H1, thereby inhibiting the expression of protein; or the translation of the genetic regulation gene through spatial block resistance to realize the selective editing of the RNA foretophyllium effect.

As of now, 9 ASOS drugs around the world have been approved by regulatory agencies such as FDA and EMA.

Vitravene was the first ASO drug that FDA approved the listing. It was jointly developed by the Ionis Pharmaceuticals and Novartis. In 1998 and 1999, the United States and the European Union were approved to treat giant cell virus retinitis. Due to the development of high -active anti -reverse transcription virus therapy, the drug was delisted in Europe and the United States in 2002 and 2006, respectively.

IONIS also has 4 ASO products that are still approved -Kynamro, Spinraza, Tegseti, Volanesors.

The remaining 4 ASO drug indications are concentrated in Du's muscle malnutrition (DMD): Sarepta Therapeutics has 3 of them; NS Pharma, a subsidiary of the Japanese New Pharmaceutical Co., Ltd.

▲ 9 ASOS drugs

SiRNA therapy: Five listed products are developed or participated by ALNYLAM

SIRNA is an oligate with dual -chain RNA, which contains 19 to 21 base pairs. In the organism, the gene silencing caused by the RNA interference (RNAI) mediated by SIRNA is an important gene expression regulatory method. It can cause the target MRNA degradation and inhibit gene expression.

RNA interference was discovered by scientists in 1998. Stanford University's Andrew Fire and Craig Mello at the University of Massachusetts have won the Nobel Prize in Physiology or Medicine in 2006 because of discovering the gene silent mechanism of SIRNA.

SIRNA was popular all over the world at the beginning of the 21st century, but due to limited technical conditions at that time, immature gene sequencing technology, poor system administration effects, drugs and side effects caused by drugs, which led to many pharmaceutical companies such as Roche, Merck, Novartis, and Pfizer Wait for the field to withdraw from this field.

Until August 2018, the FDA approved the world's first SiRNA drug Patisiran (onPattro). Observing liver cells for treating genetic transmutations of methamphetamine (HATTR) with multi -neuropathy, indicating the development step of SIRNA drugs Entering the new era. After several changes, the drug was finally pushed to the listing stage by Alnylam, which focused on SIRNA drugs.

As of now, 5 SIRNA therapies have been listed around the world, all developed or participated by Alnylam. The SIRNA therapy market has almost been monopolized by Alnylam, which brings a generous economic income to the company. In 2021, Alnylam's global net product revenue achieved $ 662 million, an increase of 83%year -on -year.

▲ 5 siRNA

In China, there are currently no SIRNA drugs. Most of them are in the phase of clinical and pre -clinical research. Representing companies include Suzhou Ruibo, Santo Pharmaceutical, Shutai Shen, Shipwang Pharmaceutical, Xi'an Rongqing and so on.

Judging from the current trend, RNA is an area with unlimited potential.

For various companies, in addition to the first layout, we need to know the eyes and continue to follow up. Just like Alnylam, the persistence of the SIRNA therapy period has given it unique fields of advantage.

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