Wednesday, May 7, 2014

Alnylam GalNAc Improvements Incremental, but Likely Enough to Beat PCSK9 Antibodies

Over the last week, Alnylam presented pre-clinical data for their new development candidates for the treatment of hypercholesterolemia (ALN-PCSsc) and liver disease related to forms of alpha-1 antitrypsin deficiency (ALN-AAT).  These candidates are based on second-generation GalNAc-conjugate chemistry that the company is now dubbing ESC (Enhanced Stabilization Chemistry).  They involve the increased use of chemical nucleic acid modifications for stability with attendant improvements in knockdown potency and duration over first-generation GalNAc conjugates such as ALN-TTRsc.  ALN-TTRsc is the lead GalNAc candidate and currently in phase II development.

Borderline first-generation GalNAcs

In a phase I study of ALN-TTRsc, potent knockdowns were achieved with about:

-60% knockdown at 2.5mg/kg;
-80% knockdown at 5.0mg/kg (ED80), and
-90% knockdown at 10.0mg/kg.

At the risk of insulting medical geneticists for oversimplifying, assume that an RNAi technology that can safely achieve an 80% target gene knockdown provides for a solid platform.  In the case where a subcutaneous route of administration is desired and/or necessary, this should ideally also fit into a 1ml injection volume which in the case of GalNAc conjugates would correspond to a 2.5mg/kg dose.

There is some controversy around acceptable injection volumes and as often is the case, increased standards are applied to RNAi Therapeutics.  I say this because drugs and drug candidates such as expected mega-blockbuster PCSK9 antibody from Amgen, AMG-145, has been administered at 2ml volumes.  In fact, to achieve once-every-4-week dosing, 6ml (3x2ml) have been administered (see Giugliano et al. 2012).

In light of this, ALN-TTRsc has failed the 1ml test, but 80% are certainly possible with this first-generation GalNAc chemistry.  There is therefore room, and in some cases a competitive need (àcompetition with more potent delivery technologies such as Tekmira’s SNALP LNPs and Arrowhead’s single molecule DPCs) for improvements in GalNAc conjugation technology.    

Second-generation data could indicate progress

In agreement with this, Alnylam is now advertising the ESC second-generation GalNAc and has presented critical non-human primate data for their new development candidates ALN-PCSsc and ALN-AAT.  Non-human primate data are ‘critical’ because the RNAi knockdown observed in monkeys typically closely predicts what will be seen in humans based on the experiences with ALN-PCS (SNALP), ALN-TTR (SNALP), and ALN-TTRsc. 

In interpreting the newly presented data, it should be noted that in the case of ALN-TTRsc, an 80% knockdown was already observed at 2.5mg/kg (and 5mg/kg) in non-human primates, but that this shifted to 5mg/kg in humans.  Numerically a relatively small difference, in practical terms an important one.   

ALN-PCSsc achieved 80% PCSK9 target gene knockdowns at 2mg/kg in a weekly multi-dose study in non-human primates.  This resulted in a highly competitive 60% LDLc lowering in the absence of statins.  Similarly impressive in light of the monoclonal antibody competition was that 80% PCSK9 knockdown and 50-60% LDLc reductions were achieved and sustained for over 3 months (!) when a single dose of 10mg/kg (2x2ml) was given.  Compare this to 57% LDLc lowering with AMG145 in a once-every-4 week regimen in the MENDEL-2 phase III study of AMG145:

-ALN-PCSsc (RNAi): 50-60% LDLc reduction, 2x2ml subcutaneous, once-every-3-months
-AMG145 (monoclonal antibody): 57% LDLc reduction, 3x2ml subcutaneous, once-every-4-weeks (phase III MENDEL-2 monotherapy study)

(Yes, I do keep an eye on cash-rich, sub-$2B market cap The Medicines Company, Alnylam’s licensee for ALN-PCSsc for this reason).

Before I get carried away with all the advantages of the RNAi platform over monoclonal antibodies for even extracellular targets such as PCSK9, in terms of GalNAc improvements, these knockdown results are very much in line with what was seen for TTR in non-human primates. 

The same applies for ALN-AAT where a single dose of 3mg/kg translated into a 60% knockdown which, based on TTR and PCSK9, will likely translate into a weekly multi-dose ED80 of 2.0-2.5mg/kg in non-human primates.

However, with the caveat of different half-lives for different target genes, the durability of the PCSK9 knockdown is quite impressive and more than what is typically seen with e.g. SNALP LNPs which have historically utilized minimally modified RNAi triggers.  Such triggers may be turned over more rapidly in liver cells.

Similarly, the RNAi trigger sequence in the TTR development candidate is an extraordinarily potent one with low single-digit picomolar EC50 potency in tissue culture.  It is therefore possible that equivalent animal potencies have now been achieved with less potent sequences meaning that the underlying delivery technology has improved.

It’s been fascinating to watch the various delivery platforms, and indeed RNaseH antisense, compete over the years and pushing each other to new heights.  In this context, I am anxiously waiting for Arrowhead’s presentation at next week’s TIDES meeting with the intriguing title:  Next Generation Dynamic Polyconjugates for siRNA Delivery in vivo,”

Market commentary: I remain mostly on the sidelines.  Years ago, these scientific data would have made me jump head-first into the market with me buying all I could in the opening minutes.  These days, however, I view them as ensuring the long-term value of RNAi stocks, but fail to see how they will support share prices in the current, growth-to-value rotating trading environment for more than a trading week or so.  I am therefore speculating on a capitulation event before some of the important clinical data read-outs roll in.  


Latebloomer said...

Near the very end of Anzalone's prepared remarks of yesterday's ARWR's CC, he said the following, which is of some help as far as guidance for timing (this was among the other upcoming 2014 catalysts he mentioned):

"Importantly, we will have regular impactful events throughout the remainder of 2014 to demonstrate our progress...And lastly, we will provide updates on undisclosed programs and technological capabilities that we are targeting for 2015."

And yes, I agree, the companies in this space are pushing each other in a competitive way that is benefiting the advance of the science, and likely more so than if anyone of them were in this alone.


Latebloomer said...

And to support the thought that ARWR is aiming for both subq delivery AND other DPC advances for 2015, he said this earlier in his prepared statements:

"We’re making substantial progress with additional undisclosed programs that we hope to provide guidance on in future. These include liver as well extra... targets ***and DPC formulations for both IV and subcutaneous administration***." (emphasis mine)


Anonymous said...

Do you know why are they going after PCSK9 when ANGPTL3 can do a better job in lowering LDL?

Dirk Haussecker said...

Agreed, lowering ANGPTL3 does seem to do a good job at lowering LDLc and other lipids. On the other hand, I believe one of those is HDLc. Then you have great human genetics on PCSK9.

bikerieder said...

ARWR Mgmt is just waiting on the data coming out of phase 2a. If they are out and good, they have proof of concept for their DPC-platform.
That will be the moment to fire from all cylinders!!

Anonymous said...


It would be interesting to see how you handicap the various RNAi delivery methods.

TKMR was alway considered the "gold standard" due to its effectiveness and longer track record. Would you say right now this is still the case? Or do you think another delivery method has replaced it in regard to future promise?

Anonymous said...

Single dose potency of GalNAc still needs a lot of improvement, though multi dose potency and durability is very good. There seems to be no further improvement in the single dose potency after what they reported in AT3.

It seems from their PR that the new ESC chemistry that they are using in their AT3, PCSK9sc and other programs are covered by Sirna patents. Could that be the reason why they bought Sirna from Merck?

Latebloomer said...

In the DB interview with Arrowhead's Bruce Givens this past Thursday, Dr. Givens only discussed his long-term hopes for their subq program, so it may be that that is what is being referred to when they say, "next generation DPC delivery."

I was thinking they were also targeting further improvement on the IV delivery, but perhaps not (other than there being new candidates for IV delivery).

Whatever the case, from Anzalone's prepared comments in the CC, it does sound like they are targeting 2015 (perhaps their 2nd new candidate for 2015?) for subq. when he states the words mentioned above:

"Importantly, we will have regular impactful events throughout the remainder of 2014 to demonstrate our progress...And lastly, we will provide updates on undisclosed programs ***and technological capabilities*** that we are targeting for 2015." (emphasis mine)

And yes, we'll know soon enough about all of the above...


Latebloomer said...

In my above comment, I should have said, " terms of the future, Dr. Givens only discussed..."


Latebloomer said...

After Sunday's press release by ALNY,

Key Scientific Data on Enhanced Stabilization Chemistry (ESC)-GalNAc-Conjugate Technology looks like the market is shaping up to be a good one for ALNY on Monday.


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