The GalNAc Wars

‘All roads lead to GalNAc’ was the thoughtful, almost philosophical response by Alnylam’s CEO John Maraganore when asked about the GalNAc-conjugate challenge mounted by ISIS Pharmaceuticals for gene silencing in hepatocytes. 

With 20mg per week (corresponding to less than 0.1mg/kg per week) and a much improved hepatocyte-specific biodistribution of otherwise more promiscuous phosphorothioate chemistry, GalNAc-antisense has suddenly re-emerged as a significant competitive threat to the hepatocyte-targeted RNAi delivery solutions by Alnylam, Arrowhead Research, and potentially other undisclosed efforts.  By comparison, 1^st gen GalNAc-based ALN-TTRsc by Alnylam required at least 10x more oligonucleotides to effect potent gene silencing in a phase Istudy in TTR amyloidosis. 

2^nd gen ESC GalNAc-conjugates are claimed to be significantly more potent, but I suspect that they won’t be that much more potent than GalNAc-ASOs and will have to win the GalNAc battle based on safety.  Arrowhead’s GalNAc-targeted single-molecule DPCs should still be the most potent of the bunch, but it is about time for them to advance them into the clinic as the first-in-class train is leaving the station for an increased number of targets and it is feeling the most-potent-in-class heat in its lead HBV indication that is based on 2-molecule DPC.

With GalNAcs applied in such a ubiquitous manner, you’d think that the likes of Alnylam and ISIS Pharmaceuticals, not known for sitting on their hands when it comes to claiming ownership over technologies would start flexing their IP muscles.  As I noted in a post from AsiaTIDES earlier this year, the word on the lab floors is that GalNAcs per se are an old, non-patentable free-for-all such that the IP focus should shift to other aspects of the GalNAc-targeting approach such as linker chemistries and economical manufacturing methods.

As much as it is an interesting twist that ISIS would adopt Alnylam technology to become competitive again for liver-directed gene silencing, the IP situation is intriguing given the cross-licensing relationship between the two companies.  The original arrangement going back to over a decade ago gave Alnylam access to IP from ISIS for the use in double-stranded oligonucleotide therapeutics, and in return ISIS got access to IP from Alnylam for use in single-stranded oligonucleotide therapeutics.  Whether this IP exchange includes IP that does not directly impinge on oligonucleotide chemistry, such as aspects of delivery will be a critical element in how easily an outright IP war could be triggered. 

If Regulus Therapeutics which has rights to Alnylam’s GalNAcs as evidenced by its anti-miR122 candidate is a guide, the IP exchange would be broader than just oligonucleotide chemistry.  On the other hand, I would be very surprised if strategy- and IP-savvy Alnylam did not foresee the potential perils of also giving ISIS access to its delivery technologies.

In any case, after the first verbal skirmishes, expect the saber-rattling around GalNAc to increase with IP adding a new dimension to what has largely been a battle based on potency and safety considerations.