The first company to have a self-amplifying mRNA (saRNA) approved as a COVID-19 vaccine attributes its success to perfecting the basics of manufacturing.

“saRNA has been around for years, but we’re the first to crack the puzzle of how to get to commercial manufacturing,” explained Pad Chivukula, PhD, CSO and COO at Arcturus Therapeutics.

Arcturus, whose ARCT-154 vaccine was approved  in November by Japan’s Ministry of Health, Labor and Welfare, says the company was able to get to market due to working on mRNA for rare diseases before the pandemic. “It was a natural fit for us. Everything just came together,” says Chivukula, adding that the team’s work included encapsulating the mRNA within lipid nanoparticles (LNPs). This gave the firm an advantage in developing a robust manufacturing process once the pandemic hit, he maintained.

Part of the challenge of commercializing saRNA, according to Arcturus, is the length of the molecules as their ARCT-154 vaccine molecule is almost three times longer than Moderna and Pfizer’s vaccines–14,000 bases as compared to 3–4 kilobases. “It’s among the largest molecules ever commercialized,” Chivukula explained.

Worked on the basics

Going from gram-scale manufacturing to a commercial process required the team to work on the basics, such as using a simple purification process to remove double-stranded RNAs, which can be a few kilobases long and can generate harmful immune reactions in patients.

The company also perfected techniques for how to keep the molecules stable, continues Chivukula. “It’s important to ensure stability because the molecules are so large,” he says, explaining that early in the pandemic, vaccines needed careful refrigeration and handling.

To improve stability and shelf life, the company has developed a novel lyophilization technique. Water, which is a major culprit in mRNA degradation, is removed during formulation, he pointed out. Before injection, the vaccine then merely needs reconstituting with saline.

“Lyophilization is used for a lot of protein-based drugs. What’s new is that we’re using this established process on LNPs and mRNA,” he told GEN.

Another major challenge they solved is finding the right combination of excipients to stop the nanoparticles sticking together. “It took a lot of empirical work and a couple of years to perfect the process,” he says. “But now we have a commercial process, we can use it [again on other therapies].”

The company is currently looking to bring a flu vaccine into the clinic and is working on the technology to develop future treatments for rare diseases.

“If mRNA can be used to introduce a protein that someone is missing, that’s going to be life-changing for many people. I’m positive it’s going to be a gamechanger,” he said.

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