Wave Life Sciences Achieves RNA Editing in Trial for WVE-006 in Alpha-1 Antitrypsin Deficiency
According to the company, this is the first time therapeutic RNA editing has been clinically demonstrated in humans.
Wave Life Sciences’ WVE-006, an investigational RNA editing oligonucleotide intended to treat alpha-1 antitrypsin deficiency (AATD), has demonstrated the ability to edit targeted RNA molecules in the first 2 patients treated in the phase 1b/2a RestorAATion-2 clinical trial (NCT06405633).1
The data come from the first 2 patients with “ZZ” AATD (Pi*ZZ AATD) to have been treated with WVE-006 and to have reached 57 days of follow-up. Both were treated in the study’s first single dose cohort received 200 mg of WVE-006. The patients, who normally would not produce any wild-type alpha-1 antitrypsin (M-AAT) protein because of their disease, showed a mean of 6.9 micromolars of wild-type M-AAT protein circulating in plasma at 15 days posttreatment, thus confirming that the intended editing of mutant Z-AAT mRNA had occurred. Furthermore, the M-AAT protein at this time point constituted more than 60% of the total AAT circulating in plasma. Neutrophil elastase inhibition also increased from baseline in a manner Wave deemed consistent with production of M-AAT. According to the company, this is the first time therapeutic RNA editing has been clinically demonstrated in humans.
Wave additionally pointed out that at 15 days posttreatment, mean total AAT protein was 10.8 micromolar, in contrast to the patients’ baseline measurements, at which point it was below the level of quantification. The company stated that increases from baseline in both AAT in general and M-AAT were seen as early as 3 days posttreatment and through 57 days posttreatment.
In terms of safety, there were no serious adverse events (AEs) reported, with all AEs being considered mild to moderate. This was also the case in RestorAATion-1 (NCT06186492), a separate safety-focused study being conducted in healthy volunteers. Wave characterizes WVE-006's safety profile thus far as “well-tolerated” and “favorable”.
“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, the president and chief executive officer of Wave Life Sciences, said in a statement.1 “It also unlocks and derisks 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. These initial data, alongside WVE-006’s durability and convenient subcutaneous administration, are all supportive of a best-in-class profile for WVE-006 relative to other editors and in the broader AATD space. These data also increase our confidence in our wholly owned pipeline, including our Huntingdon disease, Duchenne muscular dystrophy, and obesity programs, as well as our next RNA editing targets. We look forward to introducing the next RNA editing programs, as well as providing an update on our INHBE GalNAc-siRNA (WVE-007) program in obesity, at our Research Day on October 30.”
RestorAATion-2 is currently recruiting patients in Canada and RestorAATion-1 is recruiting patients in the United Kingdom. Wave originally announced having submitted a clinical trial application for WVE-006 in September, 2023.2 Although Wave Life Sciences did not indicate in which country the CTA was submitted at the time, in a request for comment a representative for the company told CGTLive® that the first locations for a potential clinical trial were expected to be in Australia and Europe.
“Today’s news is a giant step forward for the RNA medicines field, as it places us on a path for delivering the first-ever proof-of-mechanism clinical data in RNA editing," Bolno said in a statement issued to CGTLive in September 2023. "This promising new therapeutic modality offers the opportunity to access untapped areas of disease biology, adding to the armamentarium for addressing both rare and common diseases. In the case of AATD, WVE-006 is uniquely designed to revert the single G-to-A point mutation that commonly causes the disease. This would restore production and circulation of functional, wild-type M-AAT protein and reduce levels of mutant Z-AAT protein, thereby fixing both lung and liver complications for people living with AATD. Meanwhile, other approaches in development would only address liver or lung disease, but not both, or they would not correct the transcript, so WVE-006 has potential to transform how AATD is treated. Beyond WVE-006, which is partnered with GSK, Wave is also building a wholly owned pipeline of RNA editing therapeutics that offer similar opportunities to reimagine what’s possible for patients.”
Notably, Wave had previously been developing WVE-004, an antisense oligonucleotides that was under evaluation for the treatment of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in the phase 1b/2a FOCUS-C9 study (NCT04931862).3 Although, results from the trial announced in May 2023 showed that the therapy was well-tolerated, but provided no clinical benefit, and Wave accordingly discontinued the development of the product.
