First RNA Editing Therapy Nears Clinic as Excitement Mounts

2023-10-09

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Pictured: A 3D rendering of a messenger RNA strand/iStock, libre de droit Last month, Wave Life Sciences submitted a clinical trial application for WVE-006, which would be the first-ever RNA editing therapy to enter clinical development. If approved, the company plans to dose the first patients by the end of this year and have data in 2024. “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 oder to treat alpha-1 antitrypsin deficiency (AATD)–related lung or liver disease alpha-1 antitrypsin deficiency (AATD)–related lung or liver disease. Paul Bolno “It’s unique because we’re taking a broken protein, we’re fixing it, and we’re showing that when you fix the transcript, you get restored levels of protein and that protein is functional,” Bolno said. “We’re going to responsibly bring the first program into the clinic that we believe has the pro change how patients are treated.” WVE-006 relies on RNA editing instead of DNA editing. Bolno stressed that RNA editing is inherently safer to test since it is reversible and does not permanently alter the genetic code. Wave has shown that the program does not produce any bystander edits, he said, meaning it doesn’t hit unintended targets around the target site or generate unintended proteins, known as isoforms. 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 pro 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 eight programs, including WVE-006. “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.” Mollie Barnes is a freelance science writer based in Los Angeles. Reach her at mollie@100yearsco.com. Follow her on Threads and Instagram @shejustlikedtogo and see more of her work at molliebarnes.contently.com.