First RNA Editing Therapy Nears Clinic as Excitement Mounts

Pictured: A 3D rendering of a messenger RNA strand/iStock, libre de droit

“What’s important [with this application] is we’re showing [that] the field can see medicine rapidly moved from ideation to the clinic,” Paul Bolno, Wave’s CEO, told BioSpace.

WVE-006 is designed to restore production and circulation of functional, wildtype alpha-1 antitrypsin (AAT) protein and reduce levels of mutant Z-AAT protein in order to treat alpha-1 antitrypsin deficiency (AATD)–related lung or liver disease.

This is in contrast to DNA editing, which can induce unintended bystander edits or immune responses, Bolno said. This all means that Wave can include healthy volunteers in its trials. “Rapidly completing volunteer cohorts will enable the initiation of patient cohorts at optimized dose levels,” Bolno said during Wave’s R&D Day on September 28.

He added that the company feels comfortable moving WVE-006 into the clinic because of the positive results from its preclinical studies and Wave’s careful characterization of the profile and chemistry of the program. In mouse models, the candidate led to restored AAT protein “well over 11 micromolar,” improvement in several markers of liver disease and inhibition of neutrophil elastase, Anne Marie Li-Kwai-Cheung, Wave’s chief development officer, said in a statement.

Industry Poised to Accelerate

Wave’s clinical trial application has generated renewed excitement around RNA editing. Salim Syed, a managing director and senior biotechnology analyst at Mizuho Group who covers the company, said the modality will continue to garner attention.

“Investors have been quite focused on WVE-006 for AATD for some time, though [they] haven’t really engaged too much with the story given it was always a bit too far away,” he told BioSpace, adding that it’s nice to finally see this program enter the clinic with data anticipated in 2024. “It has potential to be a very important readout for the company.”

Still, Syed cautioned that as with any “first” in human testing, observers will be keeping an especially close watch on safety indicators.

“With editing of any sort . . . you’d want to make sure that the editing is highly specific and there is no evidence of bystander editing,” he said. Additionally, he noted, “You’d want to understand what durability and re-dosing may look like for WVE-006 and, in general, for any RNA editing therapy.”

Daniel de Boer, founder and CEO of ProQR Therapeutics, another RNA editing biotech, also expressed enthusiasm about the progress in the field.

“We are excited about the RNA editing space and the potential for a new class of medicines to evolve and bring us closer to improving patients’ lives with this technology,” he told BioSpace.

In 2014, ProQR discovered a technology—called Axiomer—that uses naturally occurring molecular machinery within the body to mediate single nucleotide changes to RNA in a highly specific and targeted way. The company holds a broad patent estate protecting the use of oligonucleotides to recruit endogenous ADAR (Adenosine Deaminase Acting on RNA).

“Our technology has shown promising editing efficiency in many different genes, both in vitro as well as in vivo,” de Boer said. In addition to 10 targets being developed in partnership with Eli Lilly, ProQR has selected two initial targets for its wholly-owned pipeline programs. “We are well-positioned to advance our Axiomer platform over the next several months,” de Boer said, with a clear development path for its two programs, AX-0810 for cholestatic diseases and AX-1412 for cardiovascular diseases. “Both have target-specific biomarkers with strong translatability in the clinic,” he said. De Boer said the team looks forward to sharing more data on the targets in the coming months.

Lilly is not the only large biopharma company investing in RNA editing to support its pipeline. British multinational GSK is partnered with Wave on WVE-006, as well as eight other programs, which may also be in RNA editing.

“In my 30-year career of discovering and developing medicines, I’ve never witnessed such remarkable advances in our understanding of human biology and the incredible possibilities they bring to unite science and tech together to get ahead of disease,” Tony Wood, GSK’s chief scientific officer said during Wave’s R&D Day. “Right now, we find ourselves at an inflection point with RNA and its role in broader biology.”

As an example, Wood said that oligonucleotides, the tiny molecules used in Wave’s RNA editing medicine, have traditionally been used to target rare diseases but are now being researched to potentially treat more prevalent ones.

Bolno echoed this statement, predicting that a pipeline of products will begin to deliver on the power of RNA editing over the next five years, and not just for rare diseases but for prevalent ones where he noted that the reversible nature of RNA editing will be important.

“This is no longer an alternate reality,” Bolno said. “We see lots of companies trying to say, ‘Imagine the future if…’ We don’t really have to imagine. We’re delivering the future.”

PackGene is a CRO & CDMO technology company that specializes in packaging recombinant adeno-associated virus (rAAV) vectors. Since its establishment in 2014, PackGene has been a leader in the AAV vector CRO service field, providing tens of thousands of custom batches of AAV samples to customers in over 20 countries. PackGene offers a one-stop CMC solution for the early development, pre-clinical development, clinical trials, and drug approval of rAAV vector drugs for cell and gene therapy (CGT) companies that is fast, cost-effective, high-quality, and scalable. Additionally, the company provides compliant services for the GMP-scale production of AAVs and plasmids for pharmaceutical companies, utilizing five technology platforms, including the π-Alpha 293 cell AAV high-yield platform and the π-Omega plasmid high-yield platform. PackGene's mission is to make gene therapy affordable and accelerate the launch of innovative gene drugs. The company aims to simplify the challenging aspects of gene therapy development and industrialization processes and provide stable, efficient, and economical rAAV Fast Services to accelerate gene and cell therapy development efforts from discovery phase to commercialization.

Related News