One concern with the use of any drug is that it ought to be eventually
eliminated from the body. This is a
particular issue with nanoparticulate drugs for which efficacy have been the
main design criterion. To address biodegradability for Tekmira's SNALP delivery, a technology that routinely involves
un-natural lipids which may not be easily biodegradable, Alnylam has just published
on SNALP lipid-derivatives containing readily degradable ester bonds. The results show that such SNALPs are rapidly
eliminated from the body and indicate that their use can increase
the therapeutic index.
In the paper, Maier and colleagues took the (once fiercely
contested) MC3 lipid, which is part of the ALN-TTR02 formulation for which
phase II results are imminent, and tested whether the
incorporation of ester bonds at various positions in the lipid tail would
retain knockdown efficacy. The ester
bond was chosen because it was predicted to maintain the MC3 lipid geometry and
can be degraded by the ubiquitous esterases in the body. Consistent with the idea that the apparent
pKa of the head group is important for efficacy, positions were identified that
left the pKa, and consequently knockdown activity in mice largely unchanged (ED50 of <0 .01mg="" kg="" o:p="">
To confirm the prediction that the resultant SNALP particles,
economically formulated with microfluidics, were less stable than their parent
particles, plasma and tissue elimination rates as well as the generation of
turnover intermediates were tested.
Indeed, the new SNALP particles were much less stable.
What is more, at doses of more than 3mg/kg SNALP-siRNA there was a trend
towards slight elevations with the MC3 SNALP, but not with a derivative. The authors stopped short, however, to test
concentrations at which much more toxicity can be seen.
The major downside of the study, however, was that in
non-human primates, the new SNALPs had less activity than expected for MC3
SNALPs. At 0.3mg/kg, the dose at which
80-90% knockdown was observed in the phase I study of ALN-TTR02, only a 70% TTR knockdown was
achieved. Nevertheless, it is likely
that other biodegradable SNALPs optimized for primates will achieve MC3-type efficacy.
I do not expect SNALP biodegradability to become an issue
for the upcoming ALN-TTR02 phase II results.
The longer-term dosing experience with cancer RNAi Therapeutic ALN-VSP02,
however, suggested that there could be spleen toxicity with extended dosing and
at higher dose levels. The last word
from Alnylam on that issue had been that the spleen toxicity was due to
on-target activity. The paper by Maier
et al., however, leads me to believe that both explanations are still on
Alnylam’s table.
