Wave Life Sciences Announces New Data for Leading RNA Editing Capability Across Multiple Tissues and Provides Update on AATD Program During Analyst and Investor Research Webcast - Seite 2

ADAR Editing Provides Promising Treatment Approach for Alpha-1 Antitrypsin Deficiency (AATD)

• Wave’s AATD program, its first investigational ADAR editing program, uses AIMers to potentially correct the single base mutation in mRNA coded by the SERPINA1 Z allele. ADAR editing may provide an ideal approach for addressing AATD by increasing circulating levels of functional alpha-1 antitrypsin (M-AAT) protein and reducing mutant protein aggregation in the liver, thus potentially addressing both the lung and liver manifestations of the disease.
• Today Wave shared new in vivo data demonstrating durable restoration of M-AAT protein in the liver of transgenic mice with human SERPINA1 and human ADAR following initial doses of a GalNAc-conjugated SERPINA1 AIMer. Serum concentrations of human AAT protein remained at least three-fold higher over PBS control for 30 days post-last dose with the SERPINA1 AIMer.
• Wave also shared data demonstrating progress in enhancing editing activity and protein restoration following PRISM chemistry optimization.
  • These AIMers achieved mean editing of approximately 50% of SERPINA1 mRNA in vivo.
  • Also with chemistry optimization, Wave demonstrated in vivo a four-fold increase over PBS control in AAT protein restoration in serum (or more than 15 micromolar), representing an improvement over the three-fold increase achieved with Wave’s initial AIMers. Approximately 85% of circulating AAT was confirmed to be M-AAT in treated transgenic mice with human SERPINA1 and human ADAR.
• Wave’s ADAR editing appears highly specific with nominal off-target edits observed following transcriptome analysis, nor were there bystander edits observed in the SERPINA1 transcript.
• Ongoing and planned preclinical studies are assessing durability, dose response, pharmacokinetics, and pharmacodynamics. Wave also plans to assess reduction of Z-AAT aggregates in the liver and changes in liver pathology in its transgenic mouse model.
• Wave expects to have an AATD development candidate in 2022.

About PRISM
PRISM is Wave Life Sciences’ proprietary discovery and drug development platform that enables genetically defined diseases to be targeted with stereopure oligonucleotides across multiple therapeutic modalities, including silencing, splicing and editing. PRISM combines the company’s unique ability to construct stereopure oligonucleotides with a deep understanding of how the interplay among oligonucleotide sequence, chemistry and backbone stereochemistry impacts key pharmacological properties. By exploring these interactions through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, the company continues to define design principles that are deployed across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles.