Wave Life Sciences submits application for first clinical tests of a GSK-partnered RNA editing therapy

An RNA editing therapy may be headed into human testing for the first time, after Wave Life Sciences submitted an application to bring the treatment into the clinic, the company told Endpoints News in an exclusive interview.

Unlike gene editing, which uses tools such as CRISPR to make one-time, permanent changes to DNA, RNA editing therapies would correct genetic diseases by altering short-lived messenger RNA molecules. It’s akin to correcting a typo on photocopies of a document rather than altering the original.

Wave’s therapy, WVE-006, is a synthetic RNA molecule that recruits a natural enzyme in the body to change one letter to another in RNA, correcting errors that are responsible for dysfunctional proteins. The first trial would be in alpha-1 antitrypsin deficiency, or AATD, a genetic disease that affects the lungs and liver.

Many details about the AATD trial are unknown. The company said the first few trial sites would likely be in Australia and Europe, but Wave CEO Paul Bolno wouldn’t disclose which country the clinical trial application was submitted to or how many patients would be enrolled. Bolno told Endpoints that he expects dosing to begin in the fourth quarter, starting with healthy volunteers and quickly moving to AATD patients. Results would arrive sometime in 2024, making Wave the frontrunner in a competitive field.

If the trial is successful, Wave’s partner GSK will be responsible for larger studies. The British pharma giant struck an expansive partnership with Wave in December 2022 that could earn the smaller Cambridge, MA-based company up to $3.3 billion in milestone payments, including up to $525 million for the AATD therapy. On Tuesday, Wave said that it would earn “substantial milestone payments” from GSK as soon as this year.

Anne-Marie Li-Kwai-Cheung

There are clues about the company’s plans. Some gene editing companies have run clinical trials entirely in Europe and New Zealand, where regulators are seemingly less restrictive. And in early August, Anne-Marie Li-Kwai-Cheung, chief development officer of Wave, told Endpoints in an interview in early August that the company could move into clinical trials more quickly outside the US.

“We’re really focused on speed,” she said. “There’s a very well-traveled pathway that we’ve used in our prior programs as well that can get this study up and running and executed.”

Success would mean a new chance for Wave, which over the last decade has pursed multiple antisense oligonucleotide drugs, yet struggled to find success in the clinic.

In May, the company said it would discontinue a once-promising drug for amyotrophic lateral sclerosis, or ALS, after an early-stage study found no benefit to patients. It similarly dropped therapies for Huntington’s disease in 2021 and Duchenne muscular disease in 2019. The company’s stock stock closed at $4.54 on Friday, a more than 90% drop since its all-time high in 2018.

‘Rewriting the code’

RNA’s pros and cons over gene editing are hypothetical. But Wave and others believe it has advantages.

Since the technology doesn’t irrevocably alter the genome, it might be safer. The therapies will require periodic dosing, which may prove to be a better business model for chronic diseases. And the transient tweaks could be a boon for common conditions where a permanent change isn’t desired, such as pain relief.

RNA editing may have the perk of simplicity, as well. CRISPR requires delivering bulky molecular machines made from bacterial proteins that cut genes, plus an RNA molecule to direct the editing. Wave’s therapy is just a synthetic RNA molecule that recruits a human enzyme called adenosine deaminase, or ADAR, to edit RNA.

For the patients with AATD, Wave is targeting the messenger RNA that encodes alpha-1 antitrypsin. The protein is normally made in the liver, secreted into the bloodstream, and used by the lungs to shield against collateral damage from immune cells fighting infections.

But in patients with AATD, a single genetic typo causes the protein to clump together — damaging the liver and leaves the lungs vulnerable. By fixing it, Wave hopes to restore enough normal protein to prevent liver damage and protect the lungs.

“We’re rewriting the code for the healthy protein,” Bolno said.

Other companies are working on different strategies for AATD, including small molecules that aim to stabilize the mutant protein, gene silencing therapies that reduce the mutant protein in the liver, and therapies that aim to replace the broken gene altogether.

Wave’s timeline could put it roughly a year ahead of Korro Bio, a prominent RNA editing startup that is also working on AATD and is planning to go public via a reverse merger in the fourth quarter. Korro expects to ask regulators to begin a clinical trial in the second half of 2024, with clinical data about a year later.

Along with Korro, other companies such as Shape Therapeutics, which is partnered with Roche, and ProQR Therapeutics, which is working with Eli Lilly, are also developing RNA editing therapies based on ADAR. And newer startups Ascidian Therapeutics and Amber Bio are developing different methods to edit large swathes of RNA code rather than individual letters.

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