Korro Bio has secured approvals in Australia to commence a Phase I/IIa clinical trial of KRRO-110, an investigational RNA-editing therapy for alpha-1 antitrypsin deficiency (AATD). The approvals were granted by the Australian Bellberry Human Research Ethics Committee (HREC) and the Therapeutic Goods Administration (TGA), paving the way for the REWRITE trial to begin.
REWRITE Trial Details
The REWRITE trial is a two-part, single and multiple-dose escalation study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KRRO-110. The trial will enroll up to 64 participants, including both healthy adults and AATD patients with the protease inhibitor ZZ (PiZZ) genotype, the most severe form of AATD. Secondary and exploratory endpoints will focus on pharmacokinetic and pharmacodynamic parameters to optimize dose selection for future studies.
Dosing of the first subject is anticipated in early 2025, with study completion expected in 2026. An interim analysis of data from PiZZ genotype participants is projected for the second half of 2025.
Addressing AATD with RNA Editing
AATD is a genetic disorder primarily caused by a mutation in the SERPINA1 gene, leading to pulmonary emphysema and hepatic cirrhosis. The most common mutation is a G-to-A missense mutation (PiZ) that reduces the quantity or impacts the functionality of the alpha-1 antitrypsin (AAT) protein, which is produced by the liver and protects the lungs. This deficiency can lead to the accumulation of abnormal AAT in the liver, causing hepatic damage over time. It is estimated to affect approximately 250,000 individuals worldwide.
KRRO-110, developed from Korro’s Oligonucleotide Promoted Editing of RNA (OPERA) platform, utilizes the body’s own adenosine deaminase acting on RNA (ADAR) enzyme to edit the SERPINA1 RNA and correct the disease-causing mutation. The therapy consists of an RNA-editing oligonucleotide encapsulated in a lipid nanoparticle (LNP) that is delivered systemically to reach the liver. By correcting the PiZ mutation, KRRO-110 aims to restore the secretion of normal AAT protein, potentially clearing protein aggregates from within liver cells and preserving lung function.
Preclinical Evidence
Pre-clinical data presented at the American Thoracic Society International Conference demonstrated that KRRO-110 achieved sustained editing efficiency of approximately 60% and increased total AAT protein levels to greater than 60uM at Week 13 in an in vivo genetic AATD mouse model. This level exceeds the minimum threshold considered to have a therapeutic impact in patients.
The Competitive Landscape
Korro Bio is not alone in pursuing gene editing approaches for AATD. Beam Therapeutics is developing BEAM-302, a base-editing therapeutic candidate designed to correct the PiZ mutation in genomic DNA. Wave Life Sciences is also developing WVE-006, a GalNAc-conjugated RNA-editing oligonucleotide designed to correct the PiZ mutation in SERPINA1 mRNA.
