Thursday, February 27, 2014

Oligonucleotide Therapeutics Companies Crowding into GalNAc-Conjugation

Following Alnylam’s achievement of making subcutaneous administration work for RNAi gene knockdown in the liver by conjugating RNAi triggers to the GalNAc sugar, antisense companies have started to copy the approach.  As RNAi Therapeutics have made great progress in targeted delivery, antisense companies are starting to realize that in order to stay competitive and improve the safety of systemic uses of antisense, they need to get away from the notion of 'naked'/unformulated delivery that relies on swamping the body with phosphorothioated oligonucleotides.

This has become apparent at the AsiaTIDES meeting here in Tokyo where both Santaris and ISIS Pharmaceuticals disclosed their great interests in GalNAc conjugation.

In collaboration with Axolabs (the part of Roche RNAi Therapeutics that was not acquired by Arrowhead Research and that had familiarity with GalNAcs), Santaris presented phosphorothioate-LNA Factor VII (liver) knockdown data showing 80% gene knockdowns in mice following a single dose of 0.1mg/kg.  Even more potent knockdowns were seen at 0.25mg/kg and above. 

In another presentation by ISIS Pharmaceuticals on their cardiovascular franchise, the company noted that they will follow up on their initial Apo(A) (‘little A’) candidate with a GalNAc-conjugated version.  With this, they expect to increase potency by up to 10-fold, thus allowing for 10-30mg (~0.15-0.45mg/kg) dosing.

This illustrates the utility of the GalNAc receptor (ASGPR) and how the competing RNAi and antisense technologies are fertilizing each other.

Regulus Therapeutics, of course, is the first antisense (anti-miR) company of sorts that has adopted GalNAc conjugation for their liver-directed programs, most notably anti-miR122 for HCV that is about to enter clinical development.  Regulus obviously has a license to GalNAc from Alnylam.  Whether this also applies to ISIS Pharmaceuticals, remains to be seen.  The word on the lab floors is that GalNAcs per se are not patent-protected, so ISIS may use an entirely different linker strategy to Alnylam just as Arrowhead Research does with its GalNAc-targeted DPCs.

What it means for Tekmira and Marina Biotech

Since some of you are following my investment strategy, here is what I think this means for the liver-directed efforts by Tekmira and Marina Biotech (both of which I own). 

Marina Biotech could obviously follow the same path as ISIS Pharmaceuticals and Santaris in adopting GalNAc conjugation with its CRN technology.  As such, there should be no change in the competitive value of CRN compared to Santaris and ISIS antisense.  It could also attach GalNAcs to their liposome-based SMARTICLES for which delivery to the liver remains to be demonstrated.  To do all this, however, Marina Biotech needs to grow and establish in-house R&D.  

For Tekmira, it means that RNaseH antisense are getting close in potency for gene knockdown compared to the 2nd gen MC3 SNALP LNPs (85-90% TTR gene knockdown in humans at 0.3mg/kg).  With the 3-fold more potent 3rd generation SNALP LNPs which should enter the clinic this or early next year (TKM-ALDH2, TKM-HBV), Tekmira should stay well ahead of its competition with the most potent gene knockdown technology for the liver.  This means more addressable diseases and in most cases higher treatment effects as well.   And if it incorporated GalNAc-conjugated lipids into their liposomes, too, maybe that would extend that lead even further.

If gene knockdown in the liver is not a great example for why you need a competitive free market economy, then I don’t know what is. And, of course, there is no better example of why you need a lab ;).


FMS said...

Dirk, from Marina's latest PR I guess French answered your question.

"Since we are transitioning from a primarily research focused company to a primarily development focused company, we intend to create a small initial footprint in the Boston area and keep our operating costs at a minimum. We will utilize contract research organizations as well as academic centers to advance our rare disease programs and therefore will require only a nominal laboratory operation until we establish a sponsored research and development collaboration with a partner. This will permit us to focus our available resources on our preclinical and clinical programs while continuing to build the premier nucleic acid therapeutics company in the rare disease sector."

Dirk Haussecker said...

'until we establish a sponsored research and development collaboration with a partner.'

FMS said...

It's a shop for over the counter tailored knockdown, and remember, it's transkingdom (Monsanto deal) so they can keep advancing the science indefinitely as they partner out. CEQ508 was always Michael's baby and the top priority, even though new clinical programs will start.

FMS said...

Let's not forget Arcturus and Mirna, the latter meaning $7M per selected target that enters development. Their IP is already far more advanced than the rest ,and sorry, SNALP included. Just take a look at Alison Silva's last slideshows that can or could be found somewhere on their site.. Now the only thing they need is a few phase I results. Disclaimer, yes, I've been invested in this thing since 2009.

Anonymous said...

$mrna can really enhance value from this point on. Very cheap IMHO.

Anonymous said...

Dirk, for a Marina or Benitec, how much in $US ball park figures is a decent lab to 1) set up, 2) run p/a (with quality staff who will do the job), in say a typical biotech hub?

And if that string is too variable, then seems to me there is a need looking for a solution, and you are quite probably better placed than most to facilitate the answer.

As you hinted, Pfizer (and be honest the big pharma R&D model in general), despite all their money, are not going to innovate some great compound with breathtaking speed and efficiency anytime soon.

Yet many small but promising biotechs can't afford a lab.

Are CRO's really the answer? My guess is as much as a baby sitter is going to make sure your kid is fully prepared for the real world.

Anonymous said...

With improving potency by competing delivery technologies, I think any advantage that any company had over other company in its delivery is getting marginal and not a significant factor any more. This is good news for patients but it will create fierce competition between all the RNAi drug developing companies. Santaris and Isis will be the winner since it will eliminate any perceived advantage that RNAi companies had in liver delivery.

Dirk Haussecker said...

'Santaris and Isis will be the winner since it will eliminate any perceived advantage that RNAi companies had in liver delivery'

As I said, knockdown potency will matter for most diseases. The difference of a 85% vs 95% knockdown e.g. is 3x the amount of insulting protein left.

Yes, it should improve the toxicity profile of ASOs (Santaris and ISIS), especially systemic tox. Not sure about the tox due to intracellular protein interaction.

Anonymous said...


Does it really make any difference if you achieve knockdown of 95% at 0.1mg/kg or at 0.5mg/kg? Both of them are very safe and well under 1ml volume of injection. Seems to me Subq will be the preferred mode of delivery going forward.

tufulipo said...

"Well. I like this one today. But I liked a different one yesterday. So stay tuned, I may like the old one again tomorrow, like I once favored this one, or I may not like any of the old ones. And pick an altogether new one.
Are you all still following me?"

Dirk Haussecker said...

'if you achieve knockdown of 95% at 0.1mg/kg or at 0.5mg/kg?'

Agreed. But what about if you can achieve 99% and more extended knockdown with the more potent tech at 0.5mg/kg?

In Asia (culture) and when it comes to docs (adherence), i.v. seems to enjoy more acceptance than subQ.

And when both methods can achieve similar knockdown, it may actually come down to the off-targeting/side-effects which are much less predictable.

Anonymous said...

how close is Isis getting to oral delivery? Could galnac aid its efforts to achieve oral delivery?

Dirk Haussecker said...

Whether ISIS, Alnylam, Arrowhead, or another company...yes, GalNAc may help in achieving oral delivery.

Anonymous said...

Will all these developments of meaningful science and statistics ever translate into meaningful commerce?
It's like we're making great progress but the underlying assumption is it all means nothing until a disease is curable or preventable. Only then will someone pay for it.
Why haven't we got a model for business where an improved state of well-being or a prevention of decline is worth something?
Every other class of drug does. All except RNAi.
Didn't you address this at TIDES, Dirk?

Unknown said...

Alnylam research and RNAi lead development vice president Dr Rachel Meyers noted that the company's pre-clinical research efforts have now led to the selection of a DC in its ALN-AAT program, which is part of its genetic medicine pipeline.

The company now plans to initiate IND-enabling studies with the goal of filing an IND or IND equivalent for ALN-AAT in mid-2015.

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