Wave claims first clinical RNA editing title in rare genetic disease

17-Oct-2024 - Last updated on 17-Oct-2024 at 13:52 GMT

Pic: getty/christolburgstedt

Wave Life Sciences reports that it has successfully carried out RNA editing in two patients with alpha-1 antitrypsin deficiency, the first time this kind of clinical RNA editing has been completed in humans according to the company.

The US-headquartered RNA biotech was founded in 2012 and launched on the Nasdaq in 2015. The announcement about its new trial sent shares up by 70% and is good news for big pharma partner GSK who will take over development of the alpha-1 antitrypsin deficiency (AATD) candidate therapy (WVE-006) after the current trial is completed.

Notably, on the same day Takeda stated they were cutting ties with Wave after they announced they would not be taking up the option to develop Wave’s Huntingdon’s disease candidate therapy further. This decision comes despite the release of good phase 1b/2a results for the Huntingdon’s therapy (WVE-003) in the summer. So far, Wave has received around $260 million from the Japanese big pharma from their collaboration, which began in 2018. Wave is now looking for new partners for this program.

Wave also announced good phase 2 results for its Duchenne muscular dystrophy candidate WVE-N531 earlier this year and is developing therapies for obesity and other metabolic conditions.

First therapeutic RNA editing

AATD is a rare inherited genetic condition that can result in the onset of lung or liver disease between the age of 20 and 50 years. It is a heterogeneous condition, estimated to impact around 1.1 million people around the world, and the mutations and degree of alpha-1 antitrypsin deficiency varies significantly between patients.

WVE-006 is designed to treat AATD-linked lung- or liver disease or both. It is a GalNAc-conjugated, A-to-I RNA editing oligonucleotide (AIMer) administered subcutaneously.

The two individuals mentioned in the release are taking part in the ongoing RestorAATion-2 trial and have the Pi*ZZ AATD mutation. This mutation results in abnormal mRNA and the symptoms of AATD.

Following one 200mg dose of WVE-006, the researchers succeeded in restoring levels of wild-type alpha-1 antitrypsin protein (M-AAT) to those of healthy individuals carrying one copy of the mutation.

At 57 days, plasma levels of AAT were around 11 micromolar and average levels of wild-type AAT (not normally found in these individuals) were more than 60% in the two study participants.

Riding the wave

“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,” said Paul Bolno, President and CEO at Wave Life Sciences, in a press statement.

“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.”

So far WVE-006 has been well tolerated by study participants in this trial and in another with healthy volunteers, with all reported side effects at the mild-moderate level. Wave plans to release further results from this study next year.

If the transfer to GSK continues as planned after this trial, Wave could receive up to $525 million in milestone payments and tiered royalties in the future.