Wave Life Sciences Submits CTA for Alpha-1 Antitrypsin Deficiency RNA Editing Therapy WVE-006


The therapy is expected to be able to treat both the lung and liver manifestations of AATD.

Wave Life Sciences has submitted a clinical trial application (CTA) for WVE-006, an investigational RNA editing oligonucleotide intended to treat alpha-1 antitrypsin deficiency (AATD).1 Although Wave Life Sciences did not indicate in which country the CTA was submitted, in a request for comment a representative for the company told CGTLive™ that the first locations for a potential clinical trial are 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," Paul Bolno, MD, MBA, the president and chief executive officer of Wave Life Sciences, said in a statement issued to CGTLive. "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 alpha-1 antitrypsin (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.”

WVE-006, which is GalNAc-conjugated, is intended to correct for a mutation in the disease-targeted SERPINA1 gene. In the case of lung disease, WVE-006 is expected to restore production of M-AAT, which is deficient in the lungs of patients with AATD; for liver disease, WBE-006 is expected to reduce the pathological build-up of Z-AAT in liver cells. Currently, the only treatment for the lung manifestation of AATD is weekly intravenous infusions of AAT protein and the only treatment for the liver manifestation is liver transplantation. In contrast, Wave expects that WVE-006 could provide benefit in AATD lung disease, liver disease, or both, with infrequent doses. WVE-006 functions by recruiting endogenous ADAR enzymes; as such, it does not require viral particles or liposomes for delivery.

“With the submission of the first CTA for WVE-006, we have officially initiated clinical development of the industry’s first-ever RNA editing therapeutic candidate,” Anne Marie Li-Kwai-Cheung, the chief development officer at Wave Life Sciences, said in a press release.1 “We designed WVE-006 to correct the most common underlying genetic mutation that causes AATD, providing an innovative therapeutic option for individuals with lung disease, liver disease, or both. Indeed, our preclinical data support this profile, with mouse models showing restored AAT protein well above 11 micromolar, as well as improvement in several markers of liver disease and inhibition of neutrophil elastase. As a GalNAc-RNA editing oligonucleotide, WVE-006 is reversible and redosable, with potential for infrequent subcutaneous dosing. WVE-006 is highly specific with no evidence of bystander editing and, by virtue of the mechanism of action, no permanent changes to the genome that occur with DNA-targeting approaches. For these reasons, we believe WVE-006 has potential to revolutionize how AATD is treated.”

Pending clearance of the CTA, Wave expects to enroll both healthy volunteers and patients with AATD who are homozygous for the G-to-A point mutation. The study would be expected to dose healthy volunteers first, in the fourth quarter of 2023, and patients with AATD afterwards, in 2024. In patients with AATD, Wave hopes to establish proof-of-concept by using M-AAT protein levels in serum as an outcome measure. In an “R&D Day” scheduled for September 28, 2023, the company is planning to provide more information about the clinical plans. Wave is developing WVE-006 under a collaboration agreement with GSK that was announced in December 2022 and also covers 8 of GSK’s preclinical programs.1,2 Under the terms of the agreement, Wave received an upfront payment of $170 million and is eligible for multiple future milestone payments totaling up to $3.3 billion; GSK gains an exclusive global license for the WVE-006 program.

“Positive data would be a pivotal milestone for people living with AATD and would unlock the potential of RNA editing more broadly," Bolno added in the press release.1 "Additionally, WVE-006 is a foundational component of our collaboration with GSK and carries with it meaningful milestone and royalty payments, including near-term clinical milestones. RNA editing is a promising new therapeutic modality, capable of accessing untapped areas of disease biology. We are incredibly proud to be pioneers leading the way forward in RNA editing, and we plan to share more updates on AATD and other RNA editing programs during our R&D Day later this month.”

Recently, in May 2023, Wave Life Sciences announced results from a clinical trial for one of its antisense oligonucleotides, WVE-004, which was under evaluation for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).3 The results, from the phase 1b/2a FOCUS-C9 study (NCT04931862) evaluating WVE-004 as an investigational treatment for C9orf72-associated ALS and FTD (C9-ALS/FTD), showed that the therapy was well-tolerated, but provided no clinical benefit. In light of this, Wave discontinued the development of WVE-004.

1. Wave Life Sciences announces submission of first clinical trial application for WVE-006, the first-ever RNA editing clinical candidate, and plans for upcoming virtual “R&D day”. News release. Wave Life Sciences Ltd. September 5, 2023. Accessed September 5, 2023. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-submission-first-clinical-trial
2. Wave Life Sciences and GSK announce collaboration to drive discovery and development of oligonucleotide therapeutics focusing on novel genetic targets. News release. Wave Life Sciences Ltd. December 13, 2023. Accessed September 5, 2023. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-and-gsk-announce-collaboration-drive
3. Wave Life Sciences announces topline results from phase 1b/2a FOCUS-C9 study of WVE-004 for C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia. News release. Wave Life Sciences. May 23, 2023. Accessed September 5, 2023. https://finance.yahoo.com/news/wave-life-sciences-announces-topline-113000549.html
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