Joseph Payne, President & CEO,

ARCTURUS THERAPEUTICS

"The industry has only scratched the surface of mRNA treatments and is beginning to turn towards targeting hundreds of cell types."

Can you introduce us to Arcturus Therapeutics?

We are a late-stage clinical messenger RNA vaccine and therapeutics company. For vaccines, our self-amplifying RNA, or STARR, addresses dose level issues by considerably reducing dose levels. For therapeutics, we address the challenge of safe and effective delivery of mRNA with LUNAR, our lipid nanoparticle delivery technology that protects and safely transports mRNA molecules to target tissues.

Can you elaborate on how the STARR delivery technology can help create safer, more scalable and more flexible vaccines?

Conventional mRNA vaccines that enter the body through intramuscular injection express an antigen that elicits an immune response. The antigen expression usually lasts for about two to three days before the mRNA molecule degrades. Self-amplifying mRNA, however, has a longer period of expression. This longer expression period likely is crucial for vaccines to allow for significantly reduced dose levels such as the five micrograms per dose that we have achieved for our lead Covid vaccine candidate. Unlike therapeutics, vaccines are meant to be injected into large populations made of healthy individuals. The dose needs to be minimized for safety, as there is a correlation between higher dosages and higher safety risks. For example, Covid-19 vaccines have shown dose-related toxicities such as anaphylactic allergic responses or undesired heart inflammations in rare situations.

Lowering doses also has a benefit from the manufacturing point of view. A factory making five microgram doses can be more efficient than one making 100 microgram doses, thus decreasing manufacturing cost and time. In addition to a lower dose, speed is important during times like a pandemic, and this type of vaccine can be updated frequently to adapt to new disease variants. At Arcturus we have the ability to lyophilize our vaccine products and remove the water component unlike other mRNA vaccines which are shipped as frozen liquids, providing a more stable supply chain and cold chain process.

When do you anticipate Arcturus’ Covid-19 vaccine candidates will enter the market?

In 2021, we advanced ARCT-154, our lead next-generation Covid-19 vaccine candidate. It was rapidly developed and brought into Vietnam where Phases 1 to 3 clinical studies were conducted. We also have a Phase 1/2 booster trial running in Singapore and the US. We are anticipating a final decision on Emergency Use Authorization (EUA) in Vietnam.

In parallel, in the US and Singapore, we are also evaluating our vaccine candidate as a booster. The self-amplifying mRNA is providing consistent results across all variants of interest, including Omicron and the ancestral strain from Wuhan.

To what extent did Covid-19 speed up the development of mRNA-based treatments?

The pandemic created a sense of urgency that accelerated funding and access to resources from governments worldwide. Arcturus received funding from Vietnam and Singapore that enabled us to accelerate our research. Phase 1 of ARCT-154 began in August 2021 in Vietnam and nine months later, we are awaiting a determination for an EUA in Vietnam. Traditionally, drug development has been an 8–12-year process.

This acceleration has had a positive impact on conventional mRNA therapeutics and next-generation RNA technologies. Over the last two years, we moved swiftly from conventional mRNA to self-amplifying mRNA, as opposed to each one taking 10 years to develop and implement. We hope the self-amplifying mRNA will be a more durable vaccine with broader variant coverage, which is desirable as we transition into an endemic booster market.

How can the LUNAR delivery system be used for protein replacement therapies?

Unlike a five-microgram mRNA injection for vaccines, for therapeutics we have to design for systematic administration of larger doses. It is important the mRNA is pure, and the delivery technology is biodegradable. If the delivery vehicles (lipid nanoparticles or LNPs) accumulate, it can pose risks to the liver or lungs, but LUNAR lipids have been shown to degrade after about 48 hours in pre-clinical studies.

We are currently working on a potential treatment for ornithine transcarbamylase (OTC) deficiency, related to the OTC enzyme in the urea cycle that helps process proteins and ensure normal ammonia levels. We can potentially replace the OTC enzyme by delivering its mRNA to liver cells. Once delivered, nature takes over and makes functional OTC enzyme that can potentially cure the disease and may prevent the need for liver transplants. We are also working on an mRNA therapeutic that can be inhaled to access the bronchial epithelial cells to treat cystic fibrosis.

How do you see mRNA-based therapeutics evolving in the coming years?

To have a successful mRNA vaccine or therapeutic, safe delivery is crucial and must be specific to each cell type, of which there are over 200 types in our body. The industry has only scratched the surface of mRNA treatments and is beginning to turn towards targeting those hundreds of cell types.