Cholesterol-lowering RNAi Therapeutic Shocks Monoclonal Antibody Establishment

Not too long ago, RNAi Therapeutic got dumped by Big Pharma in a big way not least because of the monoclonal/recombinant protein pedigree and corresponding bias among the top dogs of these organizations.  This was most obvious with Roche and Merck when changes in their overall R&D organizations led to the loss of their last internal RNAi champions.

How times have changed. Yesterday, The Medicines Company (who have now become a natural acquisition target) and Alnylam presented data (press release here, data here) strongly suggesting that an RNAi Therapeutic will push aside the temporally more advanced monoclonal antibody competition to become the best-in-class agent in the potentially top pharmaceutical category over probably the next two decades: the inhibition of PCSK9 for the prevention of cardiovascular morbidity and mortality.

The data in support of this claim were presented yesterday at the 2015 ESC congress in London that in retrospect was apparently named in honor of the delivery technology underlying ALN-PCSsc, a so-called Enhanced Stabilization Chemistry-based RNAi conjugate.

Treatment adherence

Importantly, the single-dose part of the study showed that starting with a dose of 300mg of ALN-PCS, PCSK9 levels were flat-lined to ~25% of normal levels for at least 4-5 months and haven’t started to perk up yet by the data cut-off date for this presentation.  It is to be expected that the knockdown will be even more pronounced with repeat dosing as supported by the initial repeat-administration data (2/3 doses) showing mean PCSK9 reductions to ~15% of normal.

Since in the PCSK9 category, it is PCSK9 that is driving LDLc lowering, the ultimate aim of this therapeutic approach, similar kinetics were seen in terms of LDLc levels in the blood with reductions (and safety/tolerability profiles) comparable to that seen with the recently approved monoclonal antibodies PRALUENT (by Regeneron/Sanofi) and REPATHA (by Amgen), ~55-60%.

In the case of the monoclonal antibodies, dose administrations every two weeks is really what it takes to consistently suppress PCSK9/LDLc because their inhibitory ability is directly correlated to their amount in the blood which declines rather precipitously after drug administration.  In the case of RNAi, however, you only need minute amounts to clamp down gene expression and at least for the liver, it appears that quarterly/semi-annual dosing schedules are realistic (it also depends on target and how much it needs to be repressed; e.g. with CC5 you may need much more target gene knockdown than 58-90%).

Sticking a needle into you just 2 or 4 times a year instead of 26 times, of course, has great advantages when it comes to treatment adherence. Keeping patients on drugs is a major issue for such life-long therapies especially since the disease is not felt acutely.  This point was made repeatedly by cardiovascular disease thought leader Dr. Kastelein on the companies’conference call.  By being able to co-ordinate drug administration with routine doctor visits, it would be possible to achieve very high compliance rates thereby preventing intermittent LDL cholesterol spikes that are believed to be particularly harmful.

In other words, assuming cardiovascular outcomes to be almost entirely driven by LDLc lowering, ALN-PCSsc would/should be best-in-class in the PCSK9 category.  There are numerous examples such as Eylea in the wet AMD space where injection frequency is the main competitive driving force among competing agents (here VEGF inhibitors) that exemplify how being a best-in-class follower can be very profitable.  Let the monoclonals build the PCSK9 market for ALN-PCSsc to then take it.

Outcomes

Last but not least, the ultimate value from being different will come from the results of the cardiovascular outcomes (and actually overall survival) studies that will really unleash the wide adoption of the PCSK9 class.  Due to their similarities, there is every reason to believe that the results from the monoclonal antibodies will cluster tightly.  By contrast, for better or worse, the outcome studies from ALN-PCSsc should be notably different and given that an RNAi agent mimics the compelling human genetics behind the PCSK9 story (extreme LDLc lowering in PCSK9-mutant individuals without other apparent untowards effects such as elevated liver triglycerides etc) much more closely, I like my chances here.  

We all know about the intricate feedback mechanisms of lipid biology so that binding a player merely in the serum as the monoclonals do as opposed to removing it from both inside and outside the cell could have unanticipated consequences.  Albeit early, the preliminary data from ALN-PCSsc support that in that the percent LDLc knockdown is the same whether in the presence or absence of high-dose statins whereas that of the monoclonal antibodies becomes muted.

Having said that, expect the monoclonal antibody establishment to play the 'RNAi is different from monoclonal antibody card' lest ALN-PCS piggy-backs on the MAb CVOT results expected to come out starting in 2017.

Back to my self-imposed exile, but I couldn't resist on commenting on what could be a perfect Oligonucleotide Therapeutics storm that is building. Next up is (maybe) ARC-520 for HBV.  And yes, I'm long MDCO as if that's not obvious.

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.