The GalNAc-RNAi trigger strategy pioneered by Alnylam and
Arrowhead Research has opened up new opportunities for RNAi Therapeutics,
partly due to the fact that they may be administered subcutaneously (note: for Arrowhead that means the single
molecule DPC which is not yet in clinical development). Although the first such product candidate,
ALN-TTRsc, looks like it could be a decent drug for a severe disease such as TTR amyloidosis,
there is room for improvement both in terms of efficacy (--> injection volumes) and tolerability/safety (liver enzyme elevations, skin reactions).
It is therefore no surprise that Alnylam keeps stressing the
fact that it has improved upon ALN-TTRsc, now referring to the original GalNAc chemistry
as ‘standard chemistry’ (STC) and the improved version as ‘enhanced
stabilization chemistry’ (ESC). By
inter- and extrapolating data from various model systems and for various target genes, the
company has come up with the notion that ESC ‘has the potential’ to be around 50x more potent than STC (IR
departments know that investors will be blind to qualifiers like ‘has
the potential’).
I love it when maths meets biology.
These numbers games, of course, make little pharmacological sense, mostly due to the fact that the same delivery chemistry
can result in disparate knockdown efficacies just due to sequence and target gene differences. In addition, concluding anything about a dose response from a ~25% knockdown in a single-dose, single dose level phase I study (--> ALN-AT3) is impossible. In RNAi, a 25% knockdown can be achieved with
homeopathic drug levels and does not inform at which drug concentrations more
robust >50% knockdowns will be observed.
Apparently, Alnylam is seeing it the same way and probably has received the same criticism from other sources. It has now provided on two recent occasions much more informative datasets on the relative potencies of
STC versus ESC.
At the Cantonese Nucleic Acids Forum (CNAF) in Guangzhou,
China, in early November, Dr. Manoharan revealed that if you turn the STC of ALN-TTRsc
into an ESC, the gain is a 5x in potency. Consistent with this 5x notion is the Nair et al. paper that published 2 days ago in
JACS where the same exercise for an siRNA sequence against the murine transthyretin gene resulted in the same 5x improved potency.
Of importance to the RNAi community, the enhanced metabolic stability
was achieved by the use of phosphorothioate bonds at the 5’ ends of both the
guide and passenger strands, while the 3’ ends are protected in both
generations by phosphorothioates in the overhang (guide strand) and the GalNAc
ligand (passenger strand), respectively.
I would not necessarily have predicted that phosphorothioates were tolerated at the guide 5’ end and this could be all the material difference there
is between STC and ESC.
All eyes are now on the ALN-AT3 phase I data presentation at
the upcoming ASH meeting next Monday (abstract here).
To wit, in part A of that study, Alnylam reported a ~25% mean peak
knockdown for the 0.03mg/kg starting dose in healthy volunteers earlier this year (single dose). Although there was no dose response data and
they had failed to reach the maximum allowable AT3 knockdown of 40%, part A was
deemed a success with the study proceeding into part B in hemophilia patients
for further dose escalation and repeat dosing. First data from that part is to be revealed.
