Wave Life Sciences said today its alpha-1 antitrypsin deficiency (AATD) candidate WVE-006 succeeded in the first-ever clinical demonstration of RNA editing in humans by achieving positive proof-of-mechanism in an early-phase clinical trial.
That positive proof, Wave said, emerged from data of the first two patients with “ZZ” AATD (Pi*ZZ AATD) who were dosed with WVE-006 and reached day 57 in the Phase Ib/IIa RestorAATion-2 trial (*NCT06405633). The presence of M-AAT protein was used as confirmation of successful editing of mutant Z-AAT mRNA, since people with with Pi*ZZ AATD do not naturally produce wild-type alpha-1 antitrypsin (M-AAT) protein.
Increases in total AAT from baseline and M-AAT protein were observed as early as day 3 and through day 57, Wave said. According to the data it shared, circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT.
Mean total AAT protein increased from below the level of quantification at baseline to 10.8 micromolar at day 15—a result that, according to Wave, meets the level used by regulators as the basis of approving AAT augmentation therapies.
Increases in neutrophil elastase inhibition from baseline were consistent with production of functional M-AAT. A restoration of 50% M-AAT would be consistent with the heterozygous “MZ” genotype with low risk of AATD lung and liver disease, Wave added.
“Achieving the first-ever therapeutic RNA editing in humans is a significant milestone for our organization, for our GSK collaboration, and for the entire oligonucleotide field,” Paul Bolno, MD, MBA, Wave’s president and CEO, declared in a statement. “It also unlocks and de-risks Wave’s RNA editing platform, in light of the continued strong clinical translation of our proprietary best-in-class chemistry, including PN, stereochemistry and our N3U AIMer modification.”
“The level of mRNA editing we are observing with a single dose exceeded our expectations and we expect M-AAT levels to continue to increase with repeat dosing, based on our preclinical data,” Bolno added.
He asserted that the initial data for WVE-006, plus its durability and subcutaneous administration, all support a best-in-class profile for WVE-006 vs. editors and in the broader AATD space.
WVE-006 is a GalNAc-conjugated, subcutaneously delivered, A-to-I RNA editing oligonucleotide (AIMer) intended to treat AATD-related lung disease, liver disease, or both. Developed through Wave’s oligonucleotide chemistry platform, WVE-006 is designed to correct the single base mutation in messenger RNA (mRNA) coded by the SERPINA1 Z allele, thereby enabling restoration and circulation of functional M-AAT protein.
200,000 Individuals
An estimated 200,000 individuals with AATD in the U.S. and Europe are homozygous for the SERPINA1 Z mutation. There are no approved therapies to treat AATD, forcing many individuals living with the disease to undergo liver transplantation. Treatment options are now limited to weekly IV augmentation therapy for lung disease, which according to Wave generated more than $1.4 billion in worldwide sales last year.
WVE-006 emerged from Wave’s up-to-$3.3 billion collaboration with GlaxoSmithKline (GSK), launched in December 2022.
Under that partnership, GSK received an exclusive global license for WVE-006, in return for agreeing to pay Wave up to $225 million in development and launch milestone payments and up to $300 million in sales-related milestone payments, as well as tiered sales royalties.
All that is in addition to the $170 million upfront payment—$120 million cash and a $50 million equity investment—with which GSK launched the collaboration.
Wave said it will transfer development and commercialization responsibilities for WVE-006 to GSK after it completes RestorAATion-2, which has an estimated primary completion timeframe of July 2025, according to the trial’s page on ClinicalTrials.gov.
One attraction for GSK in partnering with Wave was that WVE-006 represented a third oligonucleotide entering GSK’s portfolio, with the potential to be a first-in-class AATD treatment for both lung and liver disease by targeting a genetic target well understood by researchers. The other two oligonucleotides are Bepirovirsen, a Phase III antisense oligonucleotide being studied for the potential treatment of chronic hepatitis B infection; and GSK4532990, a siRNA oligonucleotide targeting HSD17B13 that is in Phase II development to treat Metabolic dysfunction-associated steatohepatitis (MASH).
News of the human RNA editing proof-of-concept sent Wave’s shares skyrocketing 74% today to $14.90 from yesterday’s close of $8.56.
“These data also increase our confidence in our wholly owned pipeline, including our HD [Huntington’s disease], DMD [Duchenne muscular dystrophy] and obesity programs, as well as our next RNA editing targets,” Bolno added.
Wave is expected to reveal its next RNA targets at its Research Day, set for October 30.
