Last week, the long-awaited first publication on
ISIS’ GalNAc-targeted antisense oligonucleotides appeared in a ‘NAR Breakthrough Article’ (Prakash et al., 2014) Living up to that label, the data with RNaseH
antisense oligonucleotides (ASOs) conjugated to triantennary GalNAc sugars showed that
this strategy increases potency by nearly an order of magnitude. In combination with high-affinity chemistries
(in this case cET) that facilitate the use of short (12-14nt vs ~20nt)
oligonucleotides which has been shown to improve in vivo potency (Santaris research by Straarup et al., 2010), oral
delivery for antisense modulation of hepatic gene expression has essentially
been solved.
Moreover, the lower dosages that can now be used in
addition to the improved biodistribution profile that is now heavily slanted
away from non-hepatocytic cell types in the liver and the kidney in favor of
hepatocytes, means that the other major benefit of GalNAc-ASOs with immediate applicability is that the safety of therapeutic ASOs for liver-directed
applications will be much improved.
The conclusion that oral antisense therapeutics are just
around the corner is based on the observation that a relatively crude
caprate-based phosphorothioate oligonucleotide formulation enabled a ~10% bioavailability following
oral administration already (intravenous = 100%; Tillman et al., 2008).
This, in addition to some inter-subject variability that might have been
linked to gastric emptying times, meant that too much oligonucleotide would
have had to be administered orally with previous antisense oligonucleotides.
Granted, this first piece of GalNAc-ASO literature did
not explore oral delivery. The fact, however, that the combined use of GalNAc conjugation
with high-affinity chemistry improved parenteral ASO potency by 60-fold is predicted to
mean that oral GalNAc-cETs are already more potent (~6x) than subQ-administered
2nd gen ASOs. These have already produced impressive phase II data for
targets such as Factor XI and ApoCIII.
The potency improvement in terms of oral delivery may
actually be larger than 60-fold. This is
because oral delivery strategies such as caprate co-formulation which aim at
increasing intercellular drug permeability are size dependent. This means that there should be an added
benefit of the smaller oligonucleotide size facilitated by cET chemistry with oral delivery.
Of course, the data leave open some questions. My most pressing, applicable to both oral and
non-oral uses of GalNAc-ASOs is how the rodent data translate into non-human
primates and ultimately humans. This is
because for unconjugated phosphorothioate oligonucleotides, the potency on a
mg/kg basis improves with the size of the organism. The discussion above is based on an
assumption that GalNAc-targeting will not change that. I have been unable to make a determination yet as to whether this should hold true or not.
Other than that, the antisense weather forecast is blue
skies ahead, though with a chance of thunderstorms in the form of IP skirmishes
with their good friends over at Alnylam as they have pioneered GalNAc conjugation in
oligonucleotide therapeutics, but may now be ironically penalized for it from a
competitive point of view. Alnylam is not the type of company that just lets competitive threats happen to them.
