The genetic technology mRNA has quickly come a long way in a short period of time.
Its story dates back more than 70 years when researchers began assessing its therapeutic potential. Over the past two decades, several mRNA-focused companies were established, but despite its promise and growing interest from large pharma, success was elusive.
All that changed in 2020 when Pfizer-BioNTech and Moderna received authorization for their mRNA-based COVID-19 vaccines. The breakthroughs during the pandemic have not only been integral in preventing more COVID-19 deaths, but have also brought extensive funding to mRNA-focused companies, enabling them to extend research into mRNA vaccines and therapies across the therapeutic spectrum.
In 2021 there were 49 deals signed involving mRNA companies or assets with a combined potential value of $5.37 billion, says Daniel Chancellor, director of thought leadership at Informa Pharma Intelligence. He adds that 2022 is off to the same pace.
“The volume of deal-making for mRNA is the result of industry waking up to its potential for vaccinating against other infectious diseases, its use in cancer, and also, just more generally, mRNA as a way of producing proteins, adding to the range of different tools that we can use to produce proteins for therapeutic effects,” Chancellor says.
When Moderna received $1 billion in research funding from the U.S. government, it also helped to de-risk mRNA and showed it was a platform worth investing in, according to Dr. Corey Casper, president and CEO at Access to Advanced Health Institute (AAHI).
While several companies — large and small — have been investing in mRNA research for years, the COVID-19 vaccine successes have spawned a swath of new mRNA startups, each seeking to improve upon or copy the platform. Now there are as many as 115 different companies with mRNA assets, Informa’s database shows.
“We have companies out of China, for example, that didn't exist two years ago that are now well funded and performing such research,” Chancellor says. “We also have bigger companies looking at this space as well, because clearly the technology is validated and has broad potential. Sanofi, for example, entered the space through the acquisition of Translate Bio. CureVac, which has been in mRNA for many years, now has a number of partnerships with larger pharmaceutical companies.”
How is this flurry of mRNA-fueled action shaking out across the industry? Here’s a look at where the industry’s pipeline stands.
The mRNA pipeline
Data from Informa shows the company with the most mRNA drugs in development is Moderna, with 46, followed by BioNTech with 29, then CureVac with 19. Of the large pharma companies, Sanofi has 11 mRNA drugs in its pipeline, Pfizer 10, GSK five and AstraZeneca has four.
Moderna is advancing mRNA vaccines against additional respiratory viruses including COVID-19 booster vaccine candidates and a seasonal flu vaccine candidate (mRNA-1010). The company also recently announced that it is developing a single dose vaccine that combines a booster against COVID-19 with a booster against flu.
Chancellor says the eventual hope is that there will be a winter respiratory virus vaccine that will encompass a range of different flu strains. However, he adds that while mRNA has proven itself to be the superior technology for quickly producing and scaling up a vaccine during a pandemic, it’s not yet proven for diseases that are already endemic.
mRNA-focused companies are developing the technology in many different therapeutic areas. For example, a spokesperson for Moderna says the company’s mRNA medicines are focused on six medical areas — infectious diseases, immuno-oncology, personalized cancer vaccines, cardiovascular disease, rare diseases and autoimmune diseases.
The company is developing vaccines for different latent viruses, which remain in the body after infection and can lead to life-long medical conditions, including a phase 3 clinical trial for cytomegalovirus (CMV).
BioNTech’s most advanced mRNA pipeline is in oncology, where the company has several phase 2 programs underway, including individualized cancer immunotherapies for melanoma and adjuvant colorectal cancer. The company has 28 vaccines or therapies in research, according to Informa data.
“BioNTech have been doing this for a long time, but they also now have huge financial power to speed up development timelines and run many more and more ambitious clinical trials simultaneously,” Chancellor says.
Among the other mRNA leaders, CureVac has been conducting mRNA research for more than 20 years and, as such, is one of the earliest innovators in the field.
A more recent entrant to mRNA is Sanofi, which initially took a wait-and-see approach to mRNA technology, but has more recently invested heavily in the area, for example, acquiring clinical-stage mRNA therapeutics company Translate Bio in August 2021.
The next big mRNA breakthroughs
Speed and versatility
According to Moderna, an advantage with mRNA technology is its potential to solve problems that are difficult for traditional drug development platforms.
“Speed is one distinct differentiator,” the Moderna spokesperson says. “If we have the sequence of a virus, we can create a vaccine candidate to study in a lab in days rather than months or even years. We can also deliver vaccines against multiple viruses with a single shot. Also, with mRNA therapeutics, we can use mRNA to potentially restore the activity of missing enzymes responsible for various rare diseases with the goal of one day bringing treatment options to patients and their families.”
The benefit of the technology is its versatility and the fact that it can teach the body how to make its own medicine by instructing the body to make proteins.
“In some cases, these proteins can train the immune system to fight disease. In others, they may replace defective or missing proteins that are critical for survival,” the Moderna spokesperson says.
For its part, AAHI is taking a slightly different approach with a focus on self-amplifying RNA (saRNA) technology rather than mRNA, which the nonprofit company says offers certain advantages for next-generation vaccines.
The organization is working to modify RNA vaccines in two different ways: The first is to make them more immunogenic for infectious diseases; and the second is to make them less immunogenic as a platform against cancer.
“With infectious disease, we’re looking to make them more accessible, broadly active and durable,” Casper says. “mRNA is amazing technology, but it's not at the point right now where it's useful for global health applications. We need to improve access by making vaccines easier to manufacture, distribute and transport, which means having a product that can be kept at room temperature for long periods of time.”
Another approach AAHI is taking to improve access is through the development of a nasal spray to deliver the vaccine, addressing the concerns of those worried about getting a shot.
AAHI is also focused on a vaccine that offers broader protection. In terms of durability, Casper says the ongoing boosters are not sustainable from a public health perspective. He maintains AAHI’s technology will address this issue.
“With cancer, we’re tinkering with the type of immune response that you get from the vaccine to allow it to be more permissive of a long-lasting effect,” Casper says. “We're working on ways to tailor the RNA to continue to express its target and also changing the quality of the immune response to be one that is better at fighting tumor cells.”
Chancellor notes, however, that not enough is currently known about the intrinsic advantages and disadvantages of mRNA in cancer.
“We're at the stage where there are some phase 2 clinical trials, which will start to produce data and then we can start to answer these questions,” he says.
Gene editing combos
One other area where mRNA is being put to the test is as a means of producing proteins. Chancellor says that it is difficult to produce certain types of proteins and get them to the right parts of the body.
“mRNA offers an alternative method of doing that, so researchers could potentially use mRNA to create quite sophisticated proteins, so rather than using cell lines or bioreactors, you're using the body and its own ribosomes to create that protein,” he explains.
With this in mind, Chancellor says one really exciting use of mRNA is where it overlaps with gene therapies, using mRNA to create the protein that does the gene editing.
“With cancer, we’re tinkering with the type of immune response that you get from the vaccine to allow it to be more permissive of a long-lasting effect.”
Dr. Corey Casper
President and CEO at Access to Advanced Health Institute
One company focused in this area is Intellia Therapeutics, gene editing pioneers that have built a platform to enable modular solutions that would support the broadest possible therapeutic application of its editing and delivery technologies.
“Intellia has proprietary elements to each aspect of our platform that have been optimized for both delivery to target cells and for its specific cargo, including, but not limited to lipid nanoparticle formulation, guide mRNA and Cas9 mRNA modifications (which we have not disclosed), and manufacturing specifications, which provide Intellia with key advantages relative to other gene editing companies,” says Ian Karp, Intellia’s senior vice president, investor relations and corporate communications.
Karp notes that, unlike gene therapy, which is susceptible to waning of effect over time, genome editing using CRISPR-based technologies, which include guide mRNA and mRNA encoding for the Cas9 enzyme, is designed to address the root cause of disease and provide a durable effect after a single dose treatment.
“In addition, we can apply our CRISPR-based technology to engineer cells for treatment of cancers and autoimmune diseases,” he says.
Successes with mRNA have led many companies and academic institutions to seek out partners to advance their pipelines.
Moderna says several of its therapeutic candidates have been designed and are being tested with industry partners including Vertex, AstraZeneca, Merck, and other public and private research institutes.
In addition, the company’s mRNA Access program aims to accelerate the creation of new vaccines using mRNA technology in collaboration with global partners. Through the program, researchers beyond Moderna can take advantage of the platform to develop novel mRNA medicines for emerging and neglected infectious diseases.
Aside from its ongoing collaboration with Pfizer, BioNTech has teamed up with many other companies to advance research, including with biopharma companies of all sizes as well as universities and medical centers.
As a small nonprofit, AAHI would never have the funds to conduct definitive phase 3 trials, so Corey and his team have licensed the technology to several industry partners.
“We’ve been very careful about those partnerships, including things like very strong global access provisions and have chosen partners that can make these products in Africa,” he says.
One disappointment, Corey notes, is that the success of the vaccines has made large companies more hesitant to share information and that could hold back opportunities to create more durable vaccines.
“I think a pan-coronavirus RNA vaccine is within our grasp and the question is, why are we needing to get boosters? Well, it's because it's incredibly financially lucrative for large pharma to continue to sell you the next booster. So, whereas the scientific community together has come up with a lot of advances that can make RNA vaccines more durable, or more broadly acting or more stable at room temperature, those aren't being broadly adopted because it's not within a specific company's financial strategy,” he says.