Korro Bio To Become Third Publicly Listed ADAR Editing Company

Today, pure-play ADAR Editing Korro Bio announced that it will reverse merge into biotech shell Frequency Therapeutics (current ticker: FREQ, to be changed to KRRO).  It will thus become the 3^rd publicly traded RNA Editing company following ProQR (pure-play) and Wave Life Sciences, the latter entertaining a broader mix of oligonucleotide therapeutics modalities (ADAR editing, exon skipping, RNAi).

Following two private founding rounds of ~$210M in 2020 and 2022, the transition into the public markets which is being accompanied by another $117M cash injection from mainly existing venture backers led by Surveyor Capital and Cormorant Asset Management, is to prepare the company making the transition to the clinic.  Its lead candidate is to address both the lung and liver manifestations of alpha-1-antitrypsin disease (AATD) caused by the prevalent piZZ genotype.

Today’s development explains their surprising announcement earlier this year to adopt liposomal delivery instead of GalNAc-targeted chemically modified oligonucleotides as is practiced by industry leaders ProQR and Wave Life Sciences.  Without the prospect of a clinical candidate, such an ‘IPO’ would not have been possible. 

As I had noted in an earlier blog entry though, such a development candidate is likely to fail both from a clinical and commercial point of view.  Firstly, for AATD patients at high risk of liver disease or actually manifesting liver disease, a chronically administered LNP seems like a bad idea. Indeed, Korro Bio today revealed significant liver enzyme elevations in animal models at doses (2mg/kg) that are likely required for robust SERPINA1 editing and are substantially higher than what is used for the clinically approved MC3-based LNP formulation Patisiran in ATTR amyloidosis by RNAi Therapeutics company Alnylam.

From a competitive point of view, the LNP approach suffers from the need of frequent, possibly weekly intravenous infusions whereas less frequent (I expect monthly) subcutaneous administration schedules should be feasible with Wave’s first clinical GalNAc editing oligo and possibly less frequently as oligo chemistry advances (similar to RNAi).  As Wave is likely to be a year ahead of Korro in the clinic, this alone makes it a head-scratcher approach for a fast-follower.

As we have learned from the RNAi Therapeutics field, further stabilizing Korro’s oligonucleotide is unlikely to extend dosing frequency as LNPs release most of their cargo into the cytoplasm almost instantaneously whereas the long duration of action by oligo-conjugates is explained by their gradual release from endosomes.

There is one scenario, however, where I can see Korro Bio’s candidate to have staying power, namely in being the only approach among the ADAR Editing and CRISPR genome editing and gene therapy candidates that can successfully treat both the lung and liver manifestations of AATD by achieving >90%-type editing levels.  As we have learned from Arrowhead Pharmaceuticals' liver AATD program (partnered with Takeda), even with near complete removal of toxic alpha-1-antitrypsin expression in the liver, prolonged treatment will likely be necessary to see a robust clinical response (phase 3 involves >3 years of dosing).

It is for this reason that I view the ADAR and genome editing approaches mainly aimed at those suffering from lung disease (which RNAi cannot address), including those with mixed phenotypes.  I will discuss clinical development landscape further in my next blog entry.

What I most like about Korro Bio, a prolific IP filer, is their mix of ADAR Editing programs encompassing genetic correction for AATD and Parkinson’s (LRRK2), anti-protein aggregation (TDP43 in ALS), modulating ion channel (NAV1.7 in pain), disrupting protein-protein interaction in alcoholic hepatitis and activating kinases.  But to extract the full value from applying RNA Editing to these attractive disease areas, Korro Bio needs to catch up on oligonucleotide chemistry and designs.