As messenger RNA vaccines save lives around the world, and RNA interference drugs are greenlit for rare diseases, the field of RNA therapeutics is now moving faster than ever before.
The COVID-19 pandemic proved a turning point for the biotech companies BioNTech and Moderna, which specialize in developing technology based on messenger RNA (mRNA). The rapid approval and rollout of their Covid vaccines saved hundreds of thousands of lives, generating enormous publicity and profits for the companies and their collaborators.
“The phenomenal success of the COVID-19 mRNA vaccine development will provide acceptance of this technology and increase the interest for the general public, patients, care providers and investors alike,” said Thomas Thum, CSO and co-founder of Cardior Pharmaceuticals, a German biotech developing RNA drugs to treat heart failure.
The emerging technology behind these vaccines consists of providing our cells with the precise instructions they need to produce proteins of the coronavirus causing COVID-19. This then trains the immune system to recognize and neutralize the coronavirus. But this is not the only application of RNA technology.
Another form of RNA, called RNA interference (RNAi), is already used to treat rare conditions by selectively turning off the expression of certain faulty genes into proteins. In late 2020, for instance, the EU and US greenlit the RNAi drug Oxlumo (lumasiran) — developed by the U.S. biotech Alnylam — as the first-ever treatment for the rare kidney condition primary hyperoxaluria.
In many ways, the rapid progress of mRNA vaccines demonstrates the RNA space was already poised to take off in a big way before the pandemic. According to Nicola Gray, an RNA expert and professor at the University of Edinburgh, U.K., a combination of factors has prepared the RNA therapeutics space to be ready for prime time.
“I think what’s moved the space forward is that there’s been a lot of developments in things like stability of RNAs and delivery, that have allowed the transition from what everybody knew we could do in cells, which is really very powerful, to actually going to a whole organism.”
A long time coming
In the 1960s, mRNA was discovered to be instrumental for converting the DNA code into proteins, but decades passed before it would be considered as a potential therapeutic modality. In 1990, scientists showed that injecting mice with mRNA encoding a certain protein resulted in the animals producing the protein. This was the start of a long journey to get RNA therapeutics to the clinic.
Despite decades of research, RNA technologies have proven slow in making it to the market. “There’s been a sort of reluctance for people to get their heads into that space,” said Gray.
The first official RNA therapeutic was fomivirsen, developed by Ionis Pharmaceuticals (previously Isis Pharmaceuticals). Approved to treat cytomegalovirus retinitis in 1998, the drug — an antisense oligonucleotide — was later withdrawn because of low demand. Six years later, the FDA approved NeXstar Pharmaceuticals’ pegaptanib to treat wet age-related macular degeneration. The drug is an RNA aptamer, which blocks target proteins in a similar way to antibody drugs.
In 2006, RNAi technology started to receive a lot of attention when its discoverers, Andrew Fire and Craig Mello, received the Nobel Prize in Medicine. However, it was not until 2018 that the first RNAi drug, Alnylam’s Onpattro (patisiran), was approved to treat the rare condition hereditary transthyretin-mediated amyloidosis (hATTR).
While safety problems delayed the approval of the first RNAi drug, Alnylam has launched one such drug every year since then. The approval of Amvuttra (vutrisiran) as another treatment for hATTR last month was its latest stride forward.
“The past few years have seen recognition of RNAi come on leaps and bounds and the insights we have obtained from Onpattro and Givlaari are now fueling a new chapter for this technology,” said Brendan Martin, SVP General Manager, U.K. & Ireland and CEMEA Commercial Innovation Lead at Alnylam.
A good time for RNA therapeutics
The global pandemic has turned the life sciences industry on its head. The major mRNA developers Moderna, BioNTech and CureVac were all focusing on developing cancer therapies and vaccines before diverting resources to the development of COVID-19 vaccines. Both BioNTech and Moderna broke records with the short time it took to submit for the approval of the vaccines.
“The speed of development and the compelling evidence for remarkable safety and efficacy in a wide-ranging population, will facilitate the development of novel drug or vaccine candidates making the R&D and approval process the new standard for the future, including for other areas of RNA therapeutics,” said Thum.
But, would RNA therapeutics and vaccines have had such success if not for the pandemic?
“There were a lot of things that needed to be solved, like stability of RNAs and how to deliver them, and a lot of those things have come into place in recent years,” explained Gray. “What I can do in a cell is now moving towards what I can do in a whole organism. And that’s incredible.”
Historically, a key challenge in the field was delivering the RNA to the target cells. Lipid nanoparticles have solved some delivery issues, as they can package the RNA so it can more easily move around the body. This is becoming more sophisticated now with increasing abilities to target specific organs and cells, regardless of where the therapy is injected.
“There are ways of doing that with control elements that take advantage of the natural regulatory mechanisms within those cells, and you sort of hijack and pirate those,” explained Gray.
Another challenge has been manufacturing at scale. However, in recent years many companies seem to have cracked this issue, and RNA manufacturing services are now part of the offering of many CDMO firms.
What’s next for the RNA field?
RNA medicines are having a good year, but what is next for the field? What is still needed to make these vaccines and therapeutics truly mainstream?
“One of the challenges with RNA vaccines, as they stand at the moment, is that they are not particularly thermally stable,” Gray noted.
“Some of the ones in clinical trials are using a [freeze-drying] procedure to combat this. Moderna’s is more thermally stable than BioNTech’s vaccine, but they also use several times more RNA in the dose; that means it’s going to be more expensive to make.”
One way to get around this is to use self-replicating RNA, a technology where the RNA drug is able to produce more copies of itself once inside the body. This concept is being trialed as a Covid booster vaccine by U.S. biotech Arcturus Therapeutics. Arcturus’ vaccine isn’t yet marketed as it’s in phase 3 testing, but could end up being cheaper to produce and equally viable in the long run.
This technology also has potential for other RNA therapeutics. “If you’re going to give somebody an injection, that RNA might last two-to-three days. But if you need six weeks to repair an organ, for instance, you don’t want to be injecting somebody every couple of days,” said Gray.
A lot of RNA medicines have focused on rare diseases and cancer until now, but they are starting to expand into other areas. For example, Cardior is working to treat heart failure with a new class of non-coding RNA drug, called microRNA (miRNA), that blocks many other RNA molecules that cause cardiovascular damage at once. In August last year, Cardior raised 64 million euros ($76 million) in a Series B to fund the development of its pipeline.
Another form of RNA technology currently in development is RNA activation. The London-based company MiNA Therapeutics began a phase 2 trial of this technology in cancer earlier this year, and also plans to develop treatments for metabolic disease.
Getting regulatory authorities on board with new therapies can be a challenge, but it has become easier in recent years with both the EU’s EMA and the U.S. FDA being open to collaboration and change. The speed of the trials carried out in 2020 and the dominance of the first-generation mRNA vaccines in the public eye has certainly helped.
|RNA technology||Companies to watch|
|Antisense RNA||Ionis Pharmaceuticals, Sarepta Therapeutics|
|Small interfering RNA (siRNA)||Alnylam, Arrowhead Pharmaceuticals, Dicerna Pharmaceuticals, Silence Therapeutics|
|Messenger RNA (mRNA)||BioNTech, Moderna, CureVac, Arcturus Therapeutics|
|Micro RNA (miRNA)||Cardior Pharmaceuticals, Viridian Therapeutics|
Both Thum and Gray believe the approvals in recent years and advances in manufacturing capacity stand the RNA field in good stead.
“It’s taken a while for us to really have the tools to move forward, which has needed people from other disciplines to come in, for instance in the development of the lipid nanoparticles,” said Gray.
“Now the tools are there, the successes in preclinical work are there and I think within the next 10 years, it’s likely that we’ll see more and more coming through to the clinic, and more acceptance of [RNA] as a valid set of technologies for the treatment of clinical problems.”
This article was originally published in December 2020 and has been updated with the latest developments in RNA technology. Inline images via Shutterstock.