CAMBRIDGE, Mass. — Korro Bio, Inc., a biopharmaceutical company focused on developing a new class of genetic medicines for both rare and highly prevalent diseases, presented new data for KRRO-110 and reported progress across its RNA editing portfolio at the J.P. Morgan Healthcare Conference on January 9, 2024.
“KRRO-110 data showed the highest levels of corrected protein in a human transgenic PiZ mouse model, supporting a potentially best-in-class therapeutic for AATD patients,” said Chief Executive Officer and President, Ram Aiyar, Ph.D. “Beyond AATD, our ability to generate de novo mutations to activate a biological pathway is uncharted in the field of RNA editing. The progress we have made across our platform and pipeline underscores our commitment to bringing differentiated therapeutic options to patients with significant unmet medical needs.”
Pipeline updates
KRRO-110
As announced on December 7, 2023, Korro selected KRRO-110 as its first development candidate for the potential treatment of AATD, an inherited genetic disorder caused by single nucleotide variants (SNVs) in the SERPINA1 gene. AATD can lead to severe progressive lung disease, including emphysema and chronic obstructive pulmonary disease (COPD), and severe liver disease leading to inflammation, cirrhosis, and fibrosis. Preclinical data to date for KRRO-110 demonstrated:
– High specificity with no bystander effects in MZ human primary hepatocytes
– Intravenous administration at 2 mg/kg resulted in secretion of ~50µM functional AAT as early as 7 days post-single dose in a human transgenic PiZ mouse model
– Increase in AAT protein and the inhibition of elastase activity were sustained through week 9 when dosed every 2 weeks, demonstrating durability in mice
– Greater than 40% editing in NHPs utilizing an earlier generation oligonucleotide designed to edit a surrogate SERPINA1 RNA target site
Preclinical development of KRRO-110 is ongoing in preparation for a regulatory filing expected in the second half of 2024, with a potential interim clinical readout in the second half of 2025.
Platform Update
Korro’s proprietary RNA editing platform, OPERA™, integrates a deep understanding of adenosine deaminase acting on RNA (ADAR) enzymology with expertise in oligonucleotide chemistry, machine learning optimization of oligonucleotides and fit-for-purpose delivery. CHORDs™, or Customized High-fidelity Oligonucleotides for RNA Deamination, are single-stranded, anti-sense oligonucleotides designed to have high target efficiency and specificity by leveraging the pillars of OPERA.
– Developed proprietary oligonucleotide chemistry using structural biology insights that enhances in vivo potency and durability of CHORDs
– Computational efficiency enables rapid iteration of CHORDs across targets
– Using CHORDs, Korro achieved greater than 50% editing in vivo utilizing both a ligand-based GalNAc conjugate and an LNP-based delivery approach
Creating De Novo Mutation to Alter Protein Function
In addition to repairing pathogenic SNVs, CHORDs can be used to engineer de novo SNVs and change amino acids on proteins to endow them with desired altered properties while still preserving their broader functional capabilities. In preclinical studies, Korro has demonstrated the ability to:
– Activate a transcription factor in an undisclosed target
Demonstrated activation of a transcription factor by creating a de novo protein variant resulting in sustained downstream activity in NHPs lasting longer than 21 days, demonstrating potential to preserve transcription factor function
– Selectively modulate TDP-43 to reduce protein aggregation
TDP-43 is a protein associated with ALS, FTD and other neurodegenerative diseases. A single RNA edit to TDP-43 is predicted to lead to the synthesis of a protein variant that does not aggregate, thereby preserving normal function and protecting downstream activity essential for neuronal health
– Modulate ion channels to within physiological levels in Nav1.7
Nav1.7 is a voltage-gated sodium channel that is essential for pain sensation and electrical signaling in the central nervous system. Korro has demonstrated that site-specific changes are sufficient to decrease the activity of Nav1.7. This approach has the potential to deliver potent analgesic activity without the dose-limiting toxicities that have been observed by sodium channel blockers
About Korro
Korro is a biopharmaceutical company focused on developing a new class of genetic medicines for both rare and highly prevalent diseases using its proprietary RNA editing platform. Korro is generating a portfolio of differentiated programs that are designed to harness the body’s natural RNA editing process to effect a precise yet transient single base edit. By editing RNA instead of DNA, Korro is expanding the reach of genetic medicines by delivering additional precision and tunability, which has the potential for increased specificity and improved long-term tolerability. Using an oligonucleotide-based approach, Korro expects to bring its medicines to patients by leveraging its proprietary platform with precedented delivery modalities, manufacturing know-how, and established regulatory pathways of approved oligonucleotide drugs.
Contacts
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Glenn Silver
FINN Partners
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