Wednesday, May 21, 2014

Dicerna Should Focus on Conjugate Delivery

Barely 3 months a public company, Dicerna has yet to emerge as a distinct RNAi Therapeutics player similar to the likes of Alnylam (à subQ GalNAc), Arrowhead Research (receptor-targeted DPCs), and Tekmira (àhigh potency liposomal RNAi).  Without leveraging the potential advantages of its Dicer-substrate RNAi triggers on which it had been founded, Dicerna will be remembered by the market as not much more than an IP workaround play.

Currently, Dicerna is utilizing liposomal delivery for its lead programs in cancer and orphan disease primary hyperoxaluria 1 (PH1), a highly versatile approach, but a niche that might be better left to Tekmira.  At least for the greater good of RNAi Therapeutics investment dollars.

Instead, Dicerna should compete more directly with both Alnylam and Arrowhead in conjugate delivery.  This is because Dicer substrates allow for the liberation of the active small interfering RNA from the conjugated ligand and/or polymer backbone by Dicer directly chewing off the conjugate.  By contrast, for conjugates like current GalNAc-siRNAs or DPCs, removal of the ligand/backbone has to be accomplished via more complex or difficult-to-work-with linker chemistries including protease-sensitive linkers or disulfides.  Such removal is usually necessary to allow for efficient incorporation into the RNAi effector complex RISC. 

In fact, it may be this chemical attachment challenge that has delayed Arrowhead’s single-molecule DPCs which I am so keen seeing progress into the clinic.

Of course, similar to adopting liposomal delivery, becoming expert in conjugate delivery probably won’t happen overnight and requires the hiring of appropriate talent.  Competition for such talent ought to be fierce with both Arrowhead and and particularly hometown rival Alnylam well cashed up and even antisense company ISIS entering the field.

We have now well crossed the point that RNAi Therapeutics is ready to churn out drugs.  If each of the players were to focus on its core strengths, it would ensure that the reach of the technology will grow in a most efficient manner.  

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By Dirk Haussecker. All rights reserved.

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