Wave Life Sciences (WVE) investor relations material

Advances in ADAR RNA editing and clinical translation

• ADAR RNA editing is progressing from theoretical and preclinical stages to clinical proof, with human data now demonstrating effective mutation correction and protein restoration in alpha-1 antitrypsin deficiency (AATD).

• Clinical data show that editing can shift patients from a high-risk ZZ phenotype to a lower-risk MZ phenotype, with durable increases in functional protein and reduction in disease-driving variants.

• Editing approaches using GalNAc conjugation enable stable, durable, and efficient delivery, with ongoing studies exploring higher doses and less frequent dosing intervals.

• Regulatory approval thresholds are being defined by phenotypic outcomes and biomarker levels, with acute phase response data supporting clinical benefit.

• The field is rapidly learning from clinical translation, using human data to refine preclinical models and accelerate new target development.

Platform innovation and pipeline expansion

• Companies are leveraging foundational research to optimize oligonucleotide chemistry and engage multiple ADAR isoforms, supporting robust and durable editing.

• Preclinical data show high levels of target protein restoration and long half-lives, supporting less frequent dosing and broadening the range of treatable liver diseases.

• New targets beyond AATD, such as PNPLA3 for liver disease and NTCP for cholestatic disease, are entering clinical and preclinical pipelines, with strategies tailored to genetic and mechanistic insights.

• CNS applications are advancing, with strong endogenous ADAR expression and efficient oligonucleotide distribution demonstrated in preclinical models.

• Companies are focusing on precision edits, such as modulating protein-protein interactions, and identifying white space in the liver for future indications.

Industry perspectives and future outlook

• The field is converging on the use of GalNAc for liver delivery, with consensus that editing offers unique advantages over knockdown approaches.

• Key to broader adoption is understanding enzyme pharmacology and translation from animal models to humans, with confidence growing in ADAR's therapeutic reliability.

• Investment and regulatory focus is shifting from enzyme function to target selection and clinical proof of concept, with expectations for rapid progress based on validated chemical toolboxes.

• The technology is expected to evolve quickly, with first-generation drugs paving the way for more optimized future candidates.

• The panel anticipates that RNA editing will reach broad applicability faster than previous modalities, driven by clinical learnings and platform advances.