Wave Life Sciences has announced the first successful therapeutic RNA editing in humans with its investigational oligonucleotide, WVE-006, designed to treat alpha-1 antitrypsin deficiency (AATD). The early data, from the Phase 1b/2a RestorAATion-2 trial, showed the ability to edit targeted RNA molecules in the first two patients treated, marking a significant milestone for RNA-based therapeutics.
Clinical Evidence of RNA Editing
The data comes from two patients with “ZZ” AATD (Pi*ZZ AATD) who received a single 200 mg dose of WVE-006 and were followed for 57 days. These patients, who typically do not produce wild-type alpha-1 antitrypsin (M-AAT) protein, exhibited a mean of 6.9 micromolar of M-AAT circulating in plasma 15 days post-treatment. This confirms the successful editing of mutant Z-AAT mRNA. Furthermore, the M-AAT protein constituted over 60% of the total AAT circulating in plasma at this time point. The increase in neutrophil elastase inhibition from baseline was consistent with the production of functional M-AAT.
Impact on AATD Treatment
The company reported that total AAT protein levels increased from below quantification levels at baseline to a mean of 10.8 micromolar by day 15 post-treatment. According to Wave, this meets the threshold set by regulators for approval of AAT augmentation therapies. Increases from baseline in both total AAT and M-AAT were observed as early as day 3 and sustained through day 57.
Paul Bolno, MD, MBA, President and CEO of Wave Life Sciences, stated, “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.”
Safety and Tolerability
WVE-006 has demonstrated a favorable safety profile, with no serious adverse events reported. All adverse events were considered mild to moderate, consistent with findings from the RestorAATion-1 study in healthy volunteers.
WVE-006 and the Treatment of AATD
WVE-006, a GalNAc-conjugated, subcutaneously delivered A-to-I RNA editing oligonucleotide (AIMer), aims to address both lung and liver complications associated with AATD. It is designed to correct the single base mutation in messenger RNA (mRNA) coded by the SERPINA1 Z allele, thereby restoring the production and circulation of functional M-AAT protein.
Market and Future Development
An estimated 200,000 individuals in the U.S. and Europe are homozygous for the SERPINA1 Z mutation. Current treatment options are limited to weekly IV augmentation therapy for lung disease, which generated over $1.4 billion in worldwide sales last year. Wave anticipates transferring development and commercialization responsibilities for WVE-006 to GSK upon completion of the RestorAATion-2 trial.
Financial Implications
GSK holds an exclusive global license for WVE-006 and will take over development and commercialization after Wave completes the RestorAATion-2 study. Wave is eligible for up to $525 million in milestone payments and sales-based royalties.
Looking Ahead
Wave Life Sciences is expected to present further updates on its RNA editing programs at its upcoming Research Day on October 30. The company's success with WVE-006 has bolstered confidence in its broader pipeline, including programs targeting Huntington’s disease, Duchenne muscular dystrophy, and obesity.
