Tuesday, July 8, 2014

GalNAc Advance by ISIS Means Oral Oligonucleotide Therapeutics around the Corner

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.

9 comments:

Anonymous said...

And you think a triantennary sugar will survive the gut? You may want to rethink your thesis.

Dirk Haussecker said...

Good point. Haven't thought too much about stability of the sugar itself. However, given that it is not an isolated sugar but covalently attached (not sure how/whether enzymes will get to that) plus the fact that the pill formulation will provide protection for most of the journey through the gut, there are good chances that enough of it will survive.

Anonymous said...

It will be more than couple of years before any oral Aso drug will enter into clinic. Then it will take at least another five years for those drugs to get to market assuming they prove to be safe and efficacious. And even if they were successful, I don't think it would be an easy task for an oral Aso drug to compete with siRNA drug that requires only a quarterly Subc injection.

Dirk Haussecker said...

Agreed, 'around the corner' in the pharmaceutical industry usually means 5-10 years and there will be room for more than 1 player, also for the liver. Oral delivery, however, adds considerable strength to a target franchise, e.g. PCSK9 or ApoCIII.

Latebloomer said...

It looks like ISIS is keen on GalNAc, but not yet keen on the current formulation:

"However, while the GN3 cluster used in our studies is efficient for enhancing ASO potency, its synthesis is lengthy and somewhat cumbersome. Ongoing work in our laboratory will determine if simplifying the GN3 scaffold to facilitate ease of manufacturing will maintain or increase potency."

Anonymous said...

Dear Liza and Dirk, there's a hole in the TKMR bucket. What can the matter be?

And right on the eve of BLT reporting its safety data after independent third party scrutiny.

Maybe something leaked and its not good. Be interesting for BLT's trading next session.

Makes you wonder what it is GENZ knows for them to pay $80ps for a piece of ALNY.

Anonymous said...

New drug for SMA shows profound effects in clinical trial

Published on Jul 11, 2014

One bright, teenage girl from Kansas City, Mo. participating in a clinical trial is showing significant improvements in symptoms of spinal muscular atrophy (SMA).
Researchers at the University of Missouri Bond Life Sciences Center have developed a promising new drug that provides hope for individuals and families living with the neurodegenerative disease.


http://youtu.be/n3r5pPfE0QQ

http://decodingscience.missouri.edu/2014/07/researchers-flex-new-muscle-in-sma-drug-development/

Anonymous said...


I don't understand why they would take down video of young girl which seemed very significant.

Researchers flex new muscle in SMA drug development
Faces of SMA
The success of therapeutics in lab experiments provides a new layer of hope for individuals and families living with the disease.
Lauren and Claire Gibbs were diagnosed on the same day.
Lauren, now 17, fit the criteria for SMA Type III, while Claire, now 16, showed symptoms of a more severe manifestation of the disease, SMA Type II.
Despite their numerous similarities, the biggest disparity between them is mobility.
Claire uses a power wheel chair while Lauren is able to use a manual chair. It’s not unusual to see Lauren being pulled along in her chair, playfully hanging onto the back of Claire’s motorized chair.
Lauren is participating in a clinical trial using a therapeutic similar to the one developed by Lorson’s lab,

and is showing significant improvement in stamina and a greater ability to walk —

a feat that wasn’t conceivable just five years ago.

http://decodingscience.missouri.edu/2014/07/researchers-flex-new-muscle-in-sma-drug-development/

Sterghios A. Moschos said...

Please read a bit about oral dosing before commenting on stability of chemistries in the gut... the GN3 chemistry, whether useful or not at scale, can be fairly easily protected. However, the crude bioavailability enhancers are just that: crude. Look at the old ISIS papers on the matter. Very variable, very unreliable.

There's better ways out there to improve oral dosing and still benefit of the GN3 improvements in targeting. What's more, given lung dosing is inactive even against low-expression targets (see Fey RA et al 2014 Inhalation toxicology; what possessed them to invest on trials with no activity in mouse or NHP's?) and the lack of GN3 receptors in the lung, I think inhalation has some mileage still.

Ping me if you want to talk more.

s.moschos@westminster.ac.uk

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