The mRNA era has arrived thanks to COVID-19. What's next in the pipeline?

Researchers originally did not think mRNA could be applied to therapeutics, but, “a few tenacious researchers and companies persisted,” according to Nature. (niphon/Getty Images)

COVID-19 wasn’t even in the picture when mRNA was developed as a new medicine, but with the regulatory runway cleared, biotechs that have been working on the tech for years are ready for liftoff.

Yes, Moderna and BioNTech are the rock stars in the business—launched to household name status with the authorization of the COVID-19 vaccines at the end of 2020. These biotechs are expected to rake in as much cash from their pandemic vaccines as AbbVie does each year for the best-selling drug of all time, Humira. The shots are expected to generate revenue of more than $40 billion for each company in 2021 and 2022, according to Mizuho Securities.

About a dozen companies besides Moderna and BioNTech are working on mRNA vaccines and therapeutics for a range of diseases from flu to cystic fibrosis. The market opportunity is huge, and Big Pharma is hungry for promising companies to snap up or make licensing deals with.

But even as the regulatory path has been cleared, the technology does have some limitations such as manufacturing, storage and dosing concerns that the industry will have to overcome as the post-COVID pipeline advances in the clinic. 

“This windfall is likely to be reinvested into new pipeline opportunities and a key question for the industry as well as investors will revolve around the probability of success for the development of new mRNA-based therapeutics in new disease settings beyond COVID-19,” Mizuho wrote about Moderna and BioNTech in a recent report on the mRNA pipeline.

The COVID-19 revenue is expected to dwindle down to merely the single-digit billions as the pandemic wanes over the next few years, but these biotechs are no one-trick ponies. Mizuho predicts that oncology, autoimmune and respiratory will be the next frontiers in mRNA. 

RELATED: Moderna is ready to spend billions in COVID-19 cash, and the famed biotech has sights set on gene editing

Moderna executives tout the company’s pipeline often—so we’ll be brief here. A cytomegalovirus candidate is the furthest along in the company’s prophylactic vaccine program, while other mid-stage assets include a personalized cancer vaccine and a localized regenerative therapeutic for the heart condition myocardial ischemia.

BioNTech, meanwhile, has dozens of assets in development for a host of common conditions: malaria, tuberculosis and even certain allergies. But where the German biotech is really making a mark is in oncology, where dozens of vaccines and therapeutics are in development. Just one is in phase 2: the Roche-partnered melanoma therapy BNT122. That drug is combined with Merck & Co.’s blockbuster Keytruda to treat metastatic melanoma in a study conducted with Roche’s Genentech.

Several Big Pharma peers have rushed to grab hold of a technology that could have incredible promise in developing therapeutics and vaccines for everything from oncology to lung diseases. Pfizer, for instance, sees mRNA taking a bigger bite out of its pipeline in the years to come after the success of the BioNTech partnership. 

RELATED: Sanofi refiles $3.2B Translate Bio buyout with FTC to allow more time for review

Sanofi, left out in the first round of developing a COVID-19 vaccine, is no longer sitting idly by. The French pharma is trying to lock in the $3.2 billion acquisition of Translate Bio to obtain the biotech’s liver and lung-focused mRNA research. Translate is conducting a phase 1/2 trial for a cystic fibrosis therapeutic called MRT5005, which has seen mixed success in the clinic. The biotech already partners with Sanofi on four preclinical vaccine candidates for COVID-19, influenza, viral pathogens and bacterial pathogens.

GlaxoSmithKline is also working on an mRNA COVID-19 vaccine with CureVac and has an early-stage rabies prophylaxis listed on its pipeline.

CureVac is trying to be a come-from-behind player in the vaccine race with two in development but has struggled in the clinic. In July, the biotech reported just 50% efficacy for one COVID-19 vaccine candidate—obviously a number that’s not going to cut it in a world where the Moderna and Pfizer-BioNTech shots are reaching efficacy in the high 90% range. 

And then there are the tiny biotechs, which maybe lack the flash of Moderna but will have a smoother path now that others have cleared the way.

RELATED: CureVac looks to subgroup to save failed COVID-19 vaccine as final analysis confirms sub-50% efficacy

Cystic fibrosis is big among the mRNA players, with Arcturus Therapeutics and ReCode Therapeutics working on a treatment each. Strand Therapeutics is striking out in oncology first, with a solid tumor candidate headed into human research in 2022.

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So that’s the state of the pipeline, but just how did we get here?

mRNA is a kind of genetic material used by the body to mimic a protein in a virus, according to the FDA. The material can be used to teach the body how to respond to an infection without injecting a dead version or other copy of the offending virus—which is how many vaccines have traditionally worked. mRNA does not alter a person’s genetic material but instead kicks the immune system into gear to fight.

The idea of making vaccines with mRNA is not new; in fact, the research goes back three decades, according to a review article recently posted by the journal Nature. The goal was to swiftly generate safe vaccines. The world saw this at work when the COVID-19 shots went from sequencing of the virus to shots in arms in less than a year in 2020.

RELATED: As Pfizer's first COVID-19 vaccine doses roll across the U.S., analysts size up the hurdles ahead

Manufacturing of mRNA vaccines can be ramped up quickly and cost-effectively, with a single bioreactor able to create almost a million individual doses in just one reaction.

Researchers originally did not think mRNA could be applied to therapeutics. But, “a few tenacious researchers and companies persisted,” according to Nature. Now, the biotech pipeline is rich with treatments made from mRNA.

BioNTech-Pfizer and Moderna helped validate the mRNA platform and spurred a lot of interest in the technology. But Nature believes the tech can tackle infectious diseases and other indications—while acknowledging some of its limitations.

COVID-19 vaccine
A patient receives a COVID-19 vaccine. (Getty/Hector Pertuz)

That’s right, mRNA isn’t perfect. We saw that, again, with the cold storage requirements that hampered the initial rollout of the COVID shots in the early days of inoculation efforts. While the companies have fine-tuned the distribution process and governments have found ways to overcome the hurdles, some regions simply can’t support vaccine programs using these first-generation mRNA shots.

Nature also points out that the duration of antibody response is still unknown: See the fierce debate over whether booster shots are necessary. More research is needed to see just how long our bodies will continue to fight off viruses like SARS-CoV-2, which causes the COVID-19 illness.

RELATED: CureVac drops Arcturus’ mRNA drug ahead of IND filing

And then there are the viral variants. Right now, the existing vaccines seem to be continuing to provide protection. But scientists are worried that the next variant could skip over the spike protein on the virus that these vaccines latch onto. That could send biotechs back to the drawing board to develop new ones—and all of us back into our socially distanced worlds.

This has already been seen with HIV, which has mutated so fast that researchers have been unsuccessful at developing a vaccine for decades. Flu vaccines also have to be recalibrated each year to catch the newest strains.

Finally, there's safety, which has seen fierce debate with the COVID-19 vaccination programs. Nature notes that mRNA vaccines have “promising safety profiles” with just mild or moderate adverse events seen during clinical trials. But other disease candidates have caused issues before, such as CureVac’s rabies vaccine, which spurred severe adverse events in 79% of participants during a study. The issue was traced to a vaccine delivery component, and the company has changed things up for subsequent candidates.

Moderna also had trouble with a phase 1 trial for the influenza H10N8 vaccine, when a high dose elicited severe adverse events. The company opted for lower doses in later trials.

RELATED: Translate Bio's mRNA fails to improve lung function in cystic fibrosis patients

With all that aside, Nature heralds the decades of research, and that to come, as a breakthrough, saying that the COVID-19 programs have “exceeded expectations and offer hope” that the pandemic will end.

“The resultant abundance of positive safety and efficacy data, together with a proven path to regulatory approval, leave us optimistic that mRNA therapeutics will transform modern medicine’s approach to vaccination, cancer immunotherapy, protein replacement therapy and beyond,” the review concluded.