The next step of mRNA: rewinding or bursting?

With the success of COVID-19 vaccines, mRNA technology has become a hot topic in the biomedical industry in recent years. According to the 2022 financial results of listed companies, Pfizer's annual revenue was $100.33 billion, of which the annual revenue of COVID-19 vaccine Comirnaty was $37.806 billion, accounting for more than one third of the total revenue. BioNTech made 17.3 billion euros from its COVID-19 vaccine, while Moderna's COVID-19 vaccine generated about $18.4 billion in sales. The three major vaccines on the market have harvested nearly 100 billion dollars in sales market.

As the epidemic fades and the COVID-19 vaccine may have entered its final carnival, where will mRNA technology go in the future? By looking at Moderna's "frequent moves" from 2023 to the present, we found some patterns for reference.

01

One of the "top ten breakthrough technologies in the world"

mRNA is a technology, to be exact, a platform technology. The basic principle of mRNA is that the modified mRNA template is injected into the cytoplasm, and the corresponding protein product is produced in the cytoplasm. After being secreted to the extracellular space, the human immune system can be stimulated to produce an immune response. The immune response is mainly achieved by introducing a secretion signal in the coding sequence of mRNA, and conventional proteins cannot cause a similar response.

In simple terms, mRNA is a "messenger" corner. In the face of different viruses, mRNA will draw the genetic information of the virus, and send it to the protein processing plant, so that the human body can produce the protein according to the "drawing", so that the human body will produce the antigen of the relevant virus, and then let the human immune system eliminate these antigens to produce antibodies, thus establishing immunity.

Elon Musk once said, "The future of medicine is mRNA. It's like a computer program that you can program to do whatever you need." Yes, the most powerful pharmaceutical plant in the world may be inside us. mRNA is essentially a code, similar to computer 0s and 1s, that tells the cell which proteins to make. With engineered mrnas, it is theoretically possible to control this process and create any desired protein - such as antibodies to immunize, enzymes to reverse rare diseases, or growth factors to repair damaged heart tissue.

Therefore, the application of mRNA is very broad. Since the 1990s, scientists began to try to use mRNA technology for disease treatment, and its important attempts have two main directions: mRNA immunotherapy and protein replacement therapy. In contrast, the development of mRNA vaccines has progressed more rapidly.

According to an article published by the Boston Consulting Group in the subsidiary of Nature, it is expected that by 2025, the global mRNA vaccine and drug development scale will reach 6.33 billion US dollars, and by 2035, the overall mRNA market size can reach 12 billion US dollars. This also indicates that mRNA will be the next "tuyere".

02

The first mRNA cancer vaccine is on the way

The treatment of COVID-19 is purely "unintentional", and tumor is the "initial heart" of mRNA technology.

Tumor vaccines use tumor antigens to induce specific anti-tumor effects through active immunization, stimulate the body's own immune protection mechanism, and achieve the role of tumor treatment or prevention of recurrence, which belongs to the category of active immunotherapy. Tumor antigens are usually divided into tumor-specific antigens (TSA) and tumor-associated antigens (TAA). TSA includes viral antigens and neoepitopes generated by nonsynonymous somatic mutations, and TAA includes tissue-specific antigens and development-specific antigens.

Recently, Moderna announced the phase 2b KEYNOTE-942 (mrNA-4157-P201) study of personalized tumor vaccine mRNA-4157 combined with Merck Sharp & Dohme Keytruda (pembrolizumab) in the treatment of patients with resected, high risk of recurrence (stage III/IV) melanoma at the 2023 AACR meeting The latest results.

The 12-month RFS rate was 83.4% (95%CI, 74.7 to 89.3) in the combination group and 77.1% (95%CI, 62.5 to 86.6) in the Keytruda monotherapy group. The 18-month RFS was 78.6% (95%CI, 69.0 to 85.6) in the combination-therapy group and 62.2% (95%CI, 46.9 to 74.3) in the Keytruda monotherapy group. This combination therapy has also previously received breakthrough therapy designation from the FDA.

Based on the positive results of the tumor vaccine, Moderna said that it will launch a phase 3 study of mRNA-4157+Keytruda combination therapy for melanoma indications in 2023, and will expand related studies to include more indications such as non-small cell lung cancer. Moderna CEO Stephen Bansel said in an interview, "This therapy should be useful in any cancer where drug K works."

Similarly, in January the British government announced a partnership with BioNTech, a German company, to test mrNA-vaccine technology to treat cancer and other diseases. The project aims to test personalised mRNA therapies in more than 10,000 patients in the UK by 2030, starting as early as this autumn.

BioNTech is part of the tumor vaccine pipeline, including BNT122, a cancer vaccine generated using the iNeST technology platform. It is used as adjuvant therapy for patients with colorectal cancer after surgery to prevent cancer recurrence; And combination with PD-1 inhibitor pembrolizumab for the first-line treatment of advanced melanoma patients.

BNT111 is a ready-to-use therapeutic vaccine manufactured with the FixVac platform. It encodes four tumor-associated antigens that are present in more than 90% of patients with melanoma and is designed to improve the prognosis of patients with melanoma by preventing T-cell exhaustion in combination with PD-1 inhibitors.

BNT112 is an mRNA vaccine for the treatment of prostate cancer. It encodes five tumor-associated antigens that are present in prostate cancer patients. It is currently in phase 1/2 clinical trials as a single agent or in combination with PD-1 inhibitors for the treatment of prostate cancer patients.

From the above "actions", it is not difficult to see that PD-1, PD-L1 and other immune checkpoint antibody drugs have achieved great success, bringing tumor therapy into the era of IO therapy, and deepening the understanding of tumor immunology for scholars in the field. Since cancer vaccines can stimulate immune responses and combine with other immunotherapies, enhancing the efficacy of immunotherapy has become an important direction of current development.

03

mRNA vaccines for infectious diseases' Coming soon '

In people's concept, vaccines are generally used for the prevention of infectious diseases: by producing and inoculating characteristic proteins or processed pathogens, so that the immune system can recognize and remember them in advance to achieve preventive effect. Coincidentally, the advantages of mRNA technology are the rapid generation of vaccines encoding pathogen antigens and the ability to encode multiple pathogens associated antigens in a single mRNA. This makes it a strong option for developing vaccines against infectious diseases.

It is understood that mRNA vaccines currently in clinical development are indicated for the prevention of infection with pathogens such as cytomegalovirus (CMV), Zika virus, respiratory syncytial virus (RSV), influenza virus, and rabies virus, in addition to COVID-19.

On April 11, Moderna updated the status of some projects in its pipeline. Of these, the Company expects to file a marketing application for its investigational RSV vaccine candidate mRNA-1345 this quarter. Previously, the Company had announced that mRNA-1345 met the primary end point in the pivotal phase 3 trial, with 83.7% efficacy for the prevention of RSV-associated lower respiratory tract illness in older adults.

In addition, Moderna's first influenza drug candidate, mRNA-1010, did not accumulate enough cases in an interim analysis to meet the prespecified statistical threshold for the phase III study, and the independent data and safety monitoring Board (DSMB) recommended continued efficacy follow-up. mRNA-1010 is one of five influenza vaccine candidates under development at Moderna and is also a quadrivalent influenza vaccine that protects against influenza caused by influenza A H1N1, A H3N2, B Victoria, and B Yamagata viruses. The vaccine produced more antibodies in humans against influenza A strains H1N1 and H3N2 than currently licensed vaccines.

In addition, Moderna announced new vaccine candidates in development for Lyme disease, mrNA-1982 and mrNA-1975, the first time the company has applied mRNA technology to a bacterial pathogen, as well as the pentavalent mrNA-1405 and trivalent mrNA-1403 vaccine candidates for norovirus (enterovirus).

It is worth mentioning that in the research and development of infectious disease vaccines, in addition to Moderna, BioNTech/ Pfizer's research and development progress is also very fast. In 2022, Pfizer announced that it had begun a phase 3 clinical trial of its mRNA influenza vaccine, a quadrivalent influenza vaccine based on modified RNA, which will recruit approximately 25,000 subjects in the United States.

It is not difficult to see that mRNA technology has achieved great success in the development of COVID-19 vaccines, which also inspires the application of mRNA technology in the development of vaccines against other infectious diseases. With the advancement of phase 3 clinical trials, the world's first mRNA vaccine for infectious disease prevention is also about to be born.

04

Delivery technology is the moat.

Among the key technologies of mRNA, delivery technology is the engine for the development of mRNA enterprises, and delivery vectors and related technologies have become a necessary place for the differentiation and innovation of major mRNA manufacturers. Most mRNA delivery methods require encapsulation of mRNA in lipid nanoparticles (LNPS), which are composed of a variety of lipids. Their formulation needs to be optimized for different delivery methods to achieve the best delivery effect.

Previously, Moderna has developed different formulations of LNP for intramuscular, intravenous and intratumoral injection. Just this year, Moderna announced a strategic partnership with GenerationBio. Under the agreement, Moderna can use the liver-targeted ctLNP developed by GenerationBio to deliver ceDNA to advance two of its liver programs as well as two immune-cell programs.

In addition, Moderna will fund all research and development activities under the collaboration and reserve the option to pursue a third program targeting immune cells or liver. GenerationBio will receive an upfront payment of up to $40 million and an equity investment of $36 million, as well as milestone payments based on future development, regulatory and commercial progress.

It is understood that GenerationBio was founded in 2016 to develop non-viral vector gene therapy using a novel cell-targeted lipid nanoparticle (ctLNP) encapsulated in closed DNA (ceDNA) to deliver gene fragments.

As early as May 2022, Moderna also updated the latest delivery technology, the mRNA delivery system for lung diseases, through the new LNP formulation to achieve drug delivery by inhalation, can target lung epithelial cells and drive the high expression of target proteins, so as to maximize the concentration of drugs in the local lung.

Moderna has partnered with Vertex to develop VX-522, an inhaled mRNA therapy expressing CFTR, for the treatment of cystic fibrosis. In December 2022, an IND application for VX-522 was approved by the FDA.

05

Enter the field of "gene editing"

At the beginning of 2023, Moderna's founders put forward a new goal for the company's development in an open letter - "maximize the potential of mRNA therapy", and in the first quarter of the year through the "successive" BD transaction project practice, of which the obvious "big action" is to enter the "gene editing" field.

On February 22, Moderna and LifeEditTherapeutics announced a strategic collaboration agreement that will combine LifeEdit's proprietary suite of gene editing technologies, including base editing, with Moderna's mRNA platform to advance gene-editing therapies for a selected set of therapeutic targets in vivo.

This represents an important step in Moderna's push into in vivo gene editing, and comes on the heels of a number of "gene editing" partnerships the company has already made:

In January 2022, Moderna and Carisma announced a partnership to combine Carisama's engineered macrophage technology with Moderna's mRNA and LNP technologies to develop in vivo chimeric antigen receptor macrophage (CAR-M) therapies.

In November 2021, Moderna announced a strategic R&D collaboration with Metagenomi focused on advancing the therapeutic use of its new gene-editing system in humans. The collaboration will combine Metagenomi's novel CRISPR gene-editing tool with Moderna's mRNA platform and lipid nanoparticle (LNP) delivery technology to develop curative treatments for patients with severe genetic diseases.

Moderna, which has frequently fallen out in the field of gene editing, has a follow-up record that deserves attention.

06

Conclusion

As an important part of the central dogma, mRNA is not only the core of biology, but also the potential of future biomedical industry development. With the maturity of technology and the expansion of indications, mRAN has walked in a new era. With the continuous realization of commercial value, global mRNA giants have also rapidly completed the original accumulation and accelerated the pace of expansion. The next trend is coming, and where should the domestic mRNA rookies go? We'll see.

References:

[1] With the advent of the commercialization era, mRNA technology is expected to usher in a golden decade, Zhongtai Securities

[2] Moderna official website

[3] New progress in the treatment of cancer, mRNA vaccine is really a play? China News Weekly

[4] Other Internet public information