mRNA and RNA biotechnology – “The software of life”
Updated: Aug 21
The recent news that BioNTech and Pfizer’s Covid-19 vaccine was more than 90 per cent effective in clinical trials has increased expectations that vaccinations will provide a way out of the coronavirus pandemic. “The good message for mankind is that we now understand that Covid-19 can be prevented by a vaccine,” Ugur Sahin, BioNTech’s chief executive, said after the announcement.
The BionNTech and Pfizer vaccine utilises ground-breaking mRNA technology, which has significantly increased global interest in biotech companies working in the mRNA space.
The mRNA technology, short for messenger RNA, is new to the vaccine scene. Conventional vaccines administer an inactivated virus, or proteins from that virus, into the body to trigger an immune response, which can prevent subsequent infection. In contrast, mRNA technology — originally developed as a cancer therapy — injects genetic instructions into the body that tell cells to make viral proteins that prime the immune system.
mRNA medicines are sets of instructions. And these instructions direct cells in the body to make proteins to prevent or fight disease. It’s actually basic human biology. DNA (deoxyribonucleic acid) is a double-stranded molecule that stores the genetic instructions your body’s cells need to make proteins. Proteins, on the other hand, are the ‘workhorses’ of the body. Nearly every function in the human body – both normal and disease-related – is carried out by one or many proteins.
mRNA is just as critical as DNA. Without mRNA, genetic code would never get used by a person's body. Proteins would never get made. And the body wouldn’t – actually couldn’t – perform its functions.
Messenger ribonucleuc acid, or mRNA for short, plays a vital role in human biology, specifically in a process known as protein synthesis. mRNA is a single-stranded molecule that carries genetic code from DNA in a cell’s nucleus to ribosomes, the cell’s protein-making machinery.
Although mRNA vaccines had been under development for several years for viruses including influenza, cytomegalovirus, HIV, rabies and Zika, the arrival of Covid-19 turbocharged the process.
Used by all living organisms to make proteins messenger RNA is one of the least explored frontiers of drug discovery. Companies such as Moderna and BioNTech are rapidly changing this. “Why are we so passionate about messenger RNA?” asked Moderna President Mr. Stephen Hodge. He said “It starts with the question of life. And in fact, all life that we know flows through messenger RNA …In our language mRNA is the software of life”
An advantage of mRNA vaccines is that they are potentially faster to develop and easier to manufacture than some other technologies. Besides the Pfizer-BioNTech vaccine, other mRNA candidates for Covid-19 are under development at Moderna in the US, CureVac in Germany, and Imperial College London in the UK. The technology means that within weeks clinical batches of vaccines can generated after the sequence encoding of the immunogen. A facility designed for mRNA production can scale-up production to manufacture vaccines against multiple targets with little adaption to processes and formulation.
Bill and Melinda Gates Foundation invested around USD $50 million in German company CureVac which is working on vaccines for COVID-19 as well as rabies, rellow fever and other infectious diseases. For a classical vaccines the antigen is introduced in the body to produce an immune response.
In the case of DNA- or RNA-based vaccines, no antigen is introduced, only the RNA or DNA containing the genetic information to produce the antigen. That is, for this specific class of vaccines, introduction of DNA and RNA provides the instructions to the body to produce the antigen itself (see below)
They can be injected in various ways (under the skin, in the vein or in lymph nodes) and then they can enter our body’s cells. Those cells will use the RNA sequence of the antigen to synthesize the protein. After this step, the mechanism is similar to classical vaccines: the antigen is presented at the surface of a subset of cells and triggers the activation of specific cells of the immune system.
Australian fund manager, Michael Frazis, whose fund is up over 110% for 12 months at 31 December 2020 is a big fan of Moderna and mRNA. He describes the company as a platform technology company as he told the Australian Finacial Review (3 Jan 2021) "Moderna is a platform company. It comes back to this idea medical science is now data science. So all they have to do is change the code on their computers, which is now specific to the spike protein on coronavirus. They can change that to anything else and there's a good chance they'll be able to develop a vaccine for that. This is a process that can be used in many different indications"
Australian biotech companies using mRNA Technology
Some Australian companies are becoming global leaders in RNA and mRNA technology.
Antisense Therapeutics Limited (ASX: ANP) and (FRA: AWY)
Antisense Therapeutics Limited recently dual-listed on the Frankfurt Stock Exchange.
The approximately 30,000 genes in human genome can be transcribed into about 85,000 different mRNA, each used in the cell as a template to synthesise a different protein. Conventional pharmaceutical drugs (small chemicals), peptides, or proteins (for example, hormones), and antibodies (which are large proteins) typically bind to the target protein directly to treat a disease.
Antisense drugs are designed to bind to the mRNA of a target protein, inhibiting the protein production process.
Antisense Therapeutics (ANP) lead drug is ATL1102, licenced from Ionis Pharmaceuticals Inc. (NASDAQ: IONS), an established leader in antisense drug development.
Ionis Pharmaceuticals is also a really interesting company with massive potential and is discussed in a separate article in this blog.
ATL1102 is a drug for Duchenne Muscular Dystrophy (DMD), which is a progressive muscular weakness, typically presented in boys. There is currently no cure for the genetic condition, but some treatments can help control symptoms.
The company recently completed Phase II trial over a six-month period, where 25 milligrams of ATL1102 was given to DMD patients aged between 10 and 18 years at the Royal Children's Hospital in Melbourne. The trial proved the safety and tolerability of the drug.
Antisense then compared the data based on the performance of upper limb function (PUL 2.0) from the phase two trial with the natural history control. These results were presented at the 25th International Annual Congress of the World Muscle Society. The results showed a statistically significant improvement in total PUL2.0, while most of the patients saw improvement or maintenance of their total PUL2.0 scores.
Rome Paediatric Neurology Professor, Eugenio Mercuri, said the results are positive and clinically relevant. "As total PUL2.0 is the key efficacy endpoint for seeking drug approval in non-ambulant patients with DMD, the comparative data further indicates ATL1102’s promising potential to provide clinically meaningful benefits in the future treatment of non-ambulant DMD patients who have very limited treatment options," he explained.
Phase IIb trials are expected to commence in Europe in 2021. These studies are expected to be an approvable study, meaning that if primary endpoints are met the drugs can be expected to be approved for sale and commercialistion.
The ASX release on Phase II Clinical Trials is below
The global market for DMD treatment therapies is around EUR 3.5 billion
The November 2020 Investor presentation can be found here
And German language Investor translation November 2020 can be downloaded here
Broker research reports independent of the company can be downloaded here
PYC Therapeutics Limited (ASX: PYC) and (FRA: PH7)
PYC Therapeutics is combining its breakthrough CPP platform with world-leading expertise in next-generation Antisense Oligonucleotides (ASOs) to create a pipeline of drugs known as CPP-ASOs. Our initial focus is to deliver to market a CPP-ASOs which treats an Inherited Retinal Disease called Retinitis Pigmentosa, the leading cause of childhood blindness.
ASOs are a leading RNA therapeutic, with 2 significant ASO drugs on the market: Biogen's Spinzara for Spinal Muscular Atrophy, and Sarepta's Exondys 51 for Duchene's Muscular Dystrophy. ASOs correct disease before it presents, including through correcting a protein deficiency or toxicity - it turns the problem off at the tap rather than just mopping up the water like many modern drugs.
ASOs correct genetic coding errors by using the cells existing machinery. In the human body, all our cells and their proteins are encoded in our DNA which makes up our genes and genome. DNA is transcribed into another molecule called RNA, which is a copy of the DNA the cell uses as instructions to make proteins. If you have a mutation in your gene, this mutation will be copied across to your RNA, and then your cell will not have the right instructions, and so it might not make the right protein. The creation of these non-functional proteins cause the genetic disease.
Retinitis pigmentosa is a genetic degenerative eye disease, one of leading causes of childhood blindness. It affects between 4,000-8,000 people in the western world and is estimated to be a $1 billion per annum market. There are currently no treatment options for the disease.
PYC’s drug program for treating retinitis pigmentosa has now shown highly effective delivery in animal models with sustained duration of effect, the ability to reverse the disease process in human cells, highly effective outcomes in complex models of the human eye, and a favourable proof of concept toxicity profile. The company recently completed a EUR 34 million share placement.
The company’s latest investor presentation, December 2020 progress report and lead drug efficacy report can be downloaded below