Korro Bio Opts for LNP in Liver-Directed Lead Program

Korro Bio yesterday announced that it would collaborate with Genevant to develop liposomally formulated oligonucleotides for the ADAR editing of alpha-1-antitrypsin in the liver.

This is a big surprise for the field since based on the successes in the oligonucleotide therapeutics industry in general and data from competitors Wave Life Sciences and ProQR in particular, it would have seemed obvious to employ GalNAc-conjugated editing oligonucleotides for alpha-1 antitrypsin-related liver disease.

Korro Bio is a privately held pure-play ADAR editing company that has raised more than $200M since 2020 and is developing oligonucleotides, as opposed to DNA-directed small editing RNAs, for mediating AàI conversion.  Given this substantial funding and what appears to be the ready availability of GalNAc, it is a big mystery to me why Korro has chosen intravenously administered LNPs and in the process is giving up substantial ownership in this program through the collaboration.

Just last month, Korro Bio and scientific founder Joshua Rosenthal published a selection strategy for efficient editing oligonucleotides.  The paper (Quiroz et al, 2023) finished off with experiments illustrating the need for extensive oligonucleotide modification, reminiscent of what ProQR and Wave Life Sciences have practiced, for effective ADAR editing.

 

Learnings from RNAi

One explanation for why Korro may have favored an intravenously over a subcutanously administered technology may be potency.  In yesterday’s press release and a recent Nature Biotechnology RNA editing industry article, the company is boasting that it wants to return serum alpha-1-antitrypsin levels to within the normal range.

A lofty goal and perhaps most readily achieved without having to balance the demands of chemical modification for stabilization purposes and inherent ADAR activation potency. 

In the earlier days of RNAi, Alnylam’s LNP-formulated Patisiran actually won out over an internal GalNAc competitor that didn’t quite have the potency and was also associated with toxicity.  Patisiran has also won the commercial race against a subcutaneously administered antisense oligonucleotide by Ionis due to superior clinical data.

Clearly, depending on the stage of chemical modification know-how with regard to a specific oligonucleotide modality, LNPs may be preferable even for the targeting of genes in hepatocytes.

Maybe Korro Bio does believe it still has a potency edge over the competition, and combining its oligonucleotides with LNPs may also get them faster into the clinic.

 

The Vivek Factor  

There is no reason to believe that in AATD an LDL receptor-targeted delivery strategy may be beneficial over an ASGPR-targeted one because of changes in receptor expression levels.

I would, however, not rule out that Korro Bio succumbed to the magic of the bewilderingly fast-talking executives from the Roivant universe (Genevant is a Roivant subsidiary).  I still cannot get over the fact that Tekmira handed over half the company plus LNPs to (now US Presidential candidate) Vivek Ramaswamy for some toxic small molecules scribbled on the back of an envelope.

When you hear Vivek on the campaign trail these days and his sharp fast talk full with twisted arguments that make your head spin, then I understand why people that for whatever reason like this energetic person may throw out reason and just want to trust this guy.  But beware: while making billions for himself and his family, he has lost many more of shareholders’ money for projects like the Alzheimer’s drug that he dug out from a dumpster and IPO’d at a valuation of over a billion USD.  I digress…

 

Until we see non-human primate data from Korro Bio and Genevant, I will count this candidate out of the race in AATD.  Whether ProQR will fill the void and throw down the gauntlet to Wave Life Science will be seen by its pipeline reveal at the end of this month.