Wave surges on first RNA editing data in humans

Shares in Wave Life Sciences rose by 74% after it reported clinical data with a pioneering new RNA-editing therapy for alpha-1 antitrypsin deficiency (AATD).

Wave claims this is the first clinical data with a therapeutic RNA-editing drug in humans, an achievement that boosted its stock, even as the news also emerged that Takeda had pulled out of a Huntington's disease alliance with the biotech.

The results come from the phase 1b/2a RestorAATion-2 study of WVE-006, a GalNAc-conjugated oligonucleotide that is designed to correct a mutation in mRNA associated with AATD that prevents patients from producing the normal 'wild-type' form of the enzyme alpha-1 antitrypsin (M-AAT).

AATD is an inherited disorder whose primary consequence is life-threatening pulmonary emphysema, resulting in irreversible destruction of the tissues supporting the function of the lungs. It also causes damage to the liver.

Two patients with homozygous "ZZ" AATD were treated with a single subcutaneous dose of WVE-006 in the study. There are an estimated 200,000 individuals living with AATD in the US and Europe with this genetic form of the disease.

M-ATT levels were below the limit of detection at baseline, but rose to around 60% of total AAT in both subjects at 15 days, reducing the proportion of forms of the enzyme that do not work properly. M-AAT stayed elevated for nearly two months (57 days), pointing to durable activity of WVE-006, which could mean it will only need to be injected every few weeks.

There were also signs that the M-AAT being produced was functional, as there was a decrease in the activity of neutrophil elastase, which causes lung damage in AATD and is inhibited by the wild-type enzyme.

No serious adverse events were observed, which is in line with what has been seen in the ongoing RestorAATion-1 study in healthy volunteers, said Wave, which expects to report data on multiple doses of WVE-006 next year.

At the moment, patients with homozygous ZZ AATD are treated with weekly intravenous infusions of alpha1-proteinase inhibitors, which can help address lung symptoms, but have no impact on the liver damage that often leads patients to require a transplant.

The results are also good news for GSK, as WVE-006 is one of the programmes covered by a wide-ranging $3 billion partnership between the two companies that started in 2022. GSK paid $170 million upfront for rights to the drug and either preclinical-stage programmes.

Under the terms of that deal, GSK will take control of WVE-006 on the success of the RestorAATion-2 study, putting Wave in line for up to $525 million in milestone payments and royalties on sales.

Wave's chief executive, Paul Bolno, said the trial data is "a significant milestone […] for the entire oligonucleotide field" and "unlocks and derisks" the company's RNA editing platform.

"This is the result of more than 10 years of oligonucleotide innovation at Wave and our resolute belief that novel chemistry is the gateway to opening up new areas of biology," he added.

Takeda waves goodbye

The excitement surrounding the data on a brand new treatment modality allowed Wave to shrug off the news that Takeda had handed back rights to Huntington's candidate WVE-003, the last remaining candidate in a multi-programme alliance signed in 2018. Takeda has paid out $260 million on various projects over that period.

Wave said in an SEC filing that it already has other parties interested in taking on WVE-003, which generated promising phase 1b/2a results earlier this year and – according to the company – represents a "potential $5 billion commercial opportunity."

The company said it "continues to expect feedback from the regulators on a potential pathway to accelerated approval for WVE-003 by the end of 2024."