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.
