An experimental therapy designed to change a single letter of short-lived mRNA molecules has corrected a genetic mutation that prevents people from making a vital protein, Wave Life Sciences announced Wednesday morning.
By mid-afternoon, its stock $WVE was up 74%.
The data come from just two patients that Wave followed for two months, but the results are the first glimpse of how RNA editing therapies might work in humans. Wave is one of several biotechs hoping the approach will provide a safe and reversible alternative to technologies like CRISPR gene editing, which make permanent changes to DNA.
Wave is testing its therapy, called WVE-006, in people with an inherited condition called alpha-1 antitrypsin deficiency, or AATD. A genetic typo prevents them from properly making a protein that is secreted from the liver and helps protect the lungs from immune cells constantly warding off infections. Wave’s therapy aims to fix that mutation in mRNA.
Both patients began making corrected versions of the AAT protein just three days after a single injection of the therapy. By day 15, the AAT protein rose from undetectable levels to 10.8 micromolars in the blood. More than 60% of that protein —6.9 micromolars — was the corrected form of AAT.
The FDA considers 11 micromolars of protein protective against the disease. Although Wave hasn’t yet hit that bar, CEO Paul Bolno told Endpoints News in an interview that he was excited by the results and thought they were “frankly surprising.” The patients were treated with the smallest of three doses that Wave plans to test in the ongoing Phase 1b/2a study, which will enroll about 24 people and is slated to wrap up in July.
“We’ve got plenty of room to explore what the upper bounds of RNA editing and protein correction are,” Bolno said.
An alternative to CRISPR
The results serve as an important reminder that CRISPR isn’t the only way to alter the genetic code. Our bodies have natural enzymes that can tweak RNA, turning an adenosine base into an inosine. This A-to-I editing, as it’s known, is conducted by an enzyme called ADAR, which gives cells an extra way to fine-tune how genes are expressed.
Wave and other companies are developing ways to control this process with synthetic RNA molecules that lasso ADAR and drag it to the precise sequence they want to edit. Last fall, Wave became the first company to ask regulators for permission to test an RNA editing therapy. The first study, in healthy volunteers, was approved in the UK, and the study in AATD patients is in Canada, according to a spokesperson.
Back in 2022, Wave partnered with GSK on its AATD therapy and could earn up to $550 million in milestone payments. GSK has the option to license the program and continue its clinical development after the study wraps up.
At least two other companies, Korro Bio and AIRNA, are also developing RNA editing therapies for AATD. It’s a good starting point for the technology since the cause of the disease is well-understood and levels of AAT protein in the blood provide a quick and easy way to see if the treatment is working at intended.
Korro, which went public through a reverse merger last year, plans to file paperwork with regulators by the end of the year for its first clinical trial, with results expected in the second half of 2025. And AIRNA, which raised $60 million in July to prepare for its own clinical study, has said it could begin tests in people next year.
Toward a more convenient therapy
Wave is testing its therapy in patients that inherited AAT mutations from both parents, leaving them susceptible to developing serious lung disease in their 30s and 40s. People who only inherit a mutation from one parent, which geneticists called a heterozygous condition, have a much lower risk of developing lung disease.
Bolno thinks that Wave’s therapy is on track to match or surpass that state. “We’re seeing basically a shift to heterozygous phenotype after a single dose,” he said.
Infusions of lab-made AAT protein can help prevent some of the lung complications of AATD, but Wave believes that its editing treatment will have the added benefit of reducing levels of mutant protein, which can aggregate in the liver and damage the organ.
The existing enzyme replacement therapies are administered through weekly intravenous infusions. Wave’s therapy is a subcutaneous injection. The company said it found healthy AAT protein in the patients 57 days after a single dose, but didn’t provide further details. In its ongoing study, Wave will give the drug to some patients every two weeks, but Bolno said early data suggest it could be spaced “monthly, quarterly or less frequently.”
Intellia Therapeutics is developing a CRISPR gene editing therapy to insert an entire new copy of the gene for AAT, which could be a one-and-done treatment. The company expects to dose its first patient later this year. So far, Intellia’s other liver-targeted CRISPR therapies appear to be safe and effective. It’s too soon to know if targeting RNA instead of DNA will have any tangible benefits for AATD patients.
Wave said there were mild and moderate side effects of its drug, but didn’t say what they were. Bolno said that prior tests of the drug in healthy volunteers suggest that “the safety profile looks clean.”